diff --git a/typo3/sysext/backend/Classes/Console/Application.php b/typo3/sysext/backend/Classes/Console/Application.php
index 07d528175b6addacbd1204b898e957888995ae5a..8feb4b90d5616f71c91986f29cbb617e7a7e25fe 100644
--- a/typo3/sysext/backend/Classes/Console/Application.php
+++ b/typo3/sysext/backend/Classes/Console/Application.php
@@ -53,6 +53,7 @@ class Application implements ApplicationInterface
 
         $this->bootstrap = Bootstrap::getInstance()
             ->initializeClassLoader($classLoader)
+            ->setRequestType(TYPO3_REQUESTTYPE_BE | TYPO3_REQUESTTYPE_CLI)
             ->baseSetup($this->entryPointPath);
 
         foreach ($this->availableRequestHandlers as $requestHandler) {
@@ -85,7 +86,6 @@ class Application implements ApplicationInterface
     protected function defineLegacyConstants()
     {
         define('TYPO3_MODE', 'BE');
-        define('TYPO3_cliMode', true);
     }
 
     /**
diff --git a/typo3/sysext/backend/Classes/Http/Application.php b/typo3/sysext/backend/Classes/Http/Application.php
index fe33adf41512b50754a5109ced7e87c09ca79a38..a48eb399afb32c0c66559895981fa466dd90067f 100644
--- a/typo3/sysext/backend/Classes/Http/Application.php
+++ b/typo3/sysext/backend/Classes/Http/Application.php
@@ -58,11 +58,9 @@ class Application implements ApplicationInterface
 
         $this->bootstrap = Bootstrap::getInstance()
             ->initializeClassLoader($classLoader)
+            ->setRequestType(TYPO3_REQUESTTYPE_BE | (!empty($_GET['ajaxID']) ? TYPO3_REQUESTTYPE_AJAX : 0))
             ->baseSetup($this->entryPointPath);
 
-        // can be done here after the base setup is done
-        $this->defineAdditionalEntryPointRelatedConstants();
-
         // Redirect to install tool if base configuration is not found
         if (!$this->bootstrap->checkIfEssentialConfigurationExists()) {
             $this->bootstrap->redirectToInstallTool($this->entryPointPath);
@@ -108,14 +106,4 @@ class Application implements ApplicationInterface
         define('TYPO3_MODE', 'BE');
     }
 
-    /**
-     * Define values that are based on the current script
-     */
-    protected function defineAdditionalEntryPointRelatedConstants()
-    {
-        // Activate "AJAX" handler when called with the GET variable ajaxID
-        if (!empty(GeneralUtility::_GET('ajaxID'))) {
-            $GLOBALS['TYPO3_AJAX'] = true;
-        }
-    }
 }
diff --git a/typo3/sysext/core/Build/UnitTestsBootstrap.php b/typo3/sysext/core/Build/UnitTestsBootstrap.php
index b5f153cb4eb8732471d602cca067f335d7e7504c..d41d734e017df2da6d5f25ceacb53f39acf316fa 100644
--- a/typo3/sysext/core/Build/UnitTestsBootstrap.php
+++ b/typo3/sysext/core/Build/UnitTestsBootstrap.php
@@ -122,7 +122,7 @@ class UnitTestsBootstrap
     }
 
     /**
-     * Defines TYPO3_MODE, TYPO3_cliMode and sets the environment variable TYPO3_CONTEXT.
+     * Defines TYPO3_MODE and sets the environment variable TYPO3_CONTEXT.
      *
      * @return UnitTestsBootstrap fluent interface
      */
@@ -131,7 +131,6 @@ class UnitTestsBootstrap
         /** @var string */
         define('TYPO3_MODE', 'BE');
         /** @var string */
-        define('TYPO3_cliMode', true);
         putenv('TYPO3_CONTEXT=Testing');
 
         return $this;
@@ -191,6 +190,7 @@ class UnitTestsBootstrap
 
         Bootstrap::getInstance()
             ->initializeClassLoader($classLoader)
+            ->setRequestType(TYPO3_REQUESTTYPE_BE | TYPO3_REQUESTTYPE_CLI)
             ->baseSetup();
 
         return $this;
diff --git a/typo3/sysext/core/Classes/Core/Bootstrap.php b/typo3/sysext/core/Classes/Core/Bootstrap.php
index 068f7c21c334347ea8aa9a6209672a74ba31dd99..9313ce9f9c85eed89e50a623c3f5cf23483cd223 100644
--- a/typo3/sysext/core/Classes/Core/Bootstrap.php
+++ b/typo3/sysext/core/Classes/Core/Bootstrap.php
@@ -116,6 +116,7 @@ class Bootstrap
         if (is_null(static::$instance)) {
             $applicationContext = getenv('TYPO3_CONTEXT') ?: (getenv('REDIRECT_TYPO3_CONTEXT') ?: 'Production');
             self::$instance = new static($applicationContext);
+            self::$instance->defineTypo3RequestTypes();
         }
         return static::$instance;
     }
@@ -185,10 +186,14 @@ class Bootstrap
      *
      * @param string $relativePathPart Relative path of entry script back to document root
      * @return Bootstrap
+     * @throws \RuntimeException when TYPO3_REQUESTTYPE was not set before, setRequestType() needs to be called before
      * @internal This is not a public API method, do not use in own extensions
      */
     public function baseSetup($relativePathPart = '')
     {
+        if (!defined('TYPO3_REQUESTTYPE')) {
+            throw new \RuntimeException('No Request Type was set, TYPO3 does not know in which context it is run.', 1450561838);
+        }
         SystemEnvironmentBuilder::run($relativePathPart);
         if (!self::$usesComposerClassLoading && ClassLoadingInformation::isClassLoadingInformationAvailable()) {
             ClassLoadingInformation::registerClassLoadingInformation();
@@ -396,8 +401,7 @@ class Bootstrap
             ->setDefaultTimezone()
             ->initializeL10nLocales()
             ->convertPageNotFoundHandlingToBoolean()
-            ->setMemoryLimit()
-            ->defineTypo3RequestTypes();
+            ->setMemoryLimit();
         if ($allowCaching) {
             $this->ensureClassLoadingInformationExists();
         }
@@ -717,8 +721,8 @@ class Bootstrap
     }
 
     /**
-     * Define TYPO3_REQUESTTYPE* constants
-     * so devs exactly know what type of request it is
+     * Define TYPO3_REQUESTTYPE* constants that can be used for developers to see if any context has been hit
+     * also see setRequestType(). Is done at the very beginning so these parameters are always available.
      *
      * @return Bootstrap
      */
@@ -729,7 +733,19 @@ class Bootstrap
         define('TYPO3_REQUESTTYPE_CLI', 4);
         define('TYPO3_REQUESTTYPE_AJAX', 8);
         define('TYPO3_REQUESTTYPE_INSTALL', 16);
-        define('TYPO3_REQUESTTYPE', (TYPO3_MODE == 'FE' ? TYPO3_REQUESTTYPE_FE : 0) | (TYPO3_MODE == 'BE' ? TYPO3_REQUESTTYPE_BE : 0) | (defined('TYPO3_cliMode') && TYPO3_cliMode ? TYPO3_REQUESTTYPE_CLI : 0) | (defined('TYPO3_enterInstallScript') && TYPO3_enterInstallScript ? TYPO3_REQUESTTYPE_INSTALL : 0) | ($GLOBALS['TYPO3_AJAX'] ? TYPO3_REQUESTTYPE_AJAX : 0));
+    }
+
+    /**
+     * Defines the TYPO3_REQUESTTYPE constant so the environment knows which context the request is running.
+     *
+     * @throws \RuntimeException if the method was already called during a request
+     * @return Bootstrap
+     */
+    public function setRequestType($requestType) {
+        if (defined('TYPO3_REQUESTTYPE')) {
+            throw new \RuntimeException('TYPO3_REQUESTTYPE has already been set, cannot be called multiple times', 1450561878);
+        }
+        define('TYPO3_REQUESTTYPE', $requestType);
         return $this;
     }
 
@@ -778,7 +794,6 @@ class Bootstrap
         unset($GLOBALS['TBE_MODULES_EXT']);
         unset($GLOBALS['TCA_DESCR']);
         unset($GLOBALS['LOCAL_LANG']);
-        unset($GLOBALS['TYPO3_AJAX']);
         return $this;
     }
 
diff --git a/typo3/sysext/core/Classes/Core/SystemEnvironmentBuilder.php b/typo3/sysext/core/Classes/Core/SystemEnvironmentBuilder.php
index e41fc44bf6db9b7b7952f39848a1023b48f48bfd..cd74bb0d36f6982ec32b2b5ec72c15ff567d6daa 100644
--- a/typo3/sysext/core/Classes/Core/SystemEnvironmentBuilder.php
+++ b/typo3/sysext/core/Classes/Core/SystemEnvironmentBuilder.php
@@ -276,7 +276,7 @@ class SystemEnvironmentBuilder
      */
     protected static function getPathThisScript()
     {
-        if (defined('TYPO3_cliMode') && TYPO3_cliMode === true) {
+        if (TYPO3_REQUESTTYPE & TYPO3_REQUESTTYPE_CLI) {
             return self::getPathThisScriptCli();
         } else {
             return self::getPathThisScriptNonCli();
diff --git a/typo3/sysext/core/Classes/FormProtection/FormProtectionFactory.php b/typo3/sysext/core/Classes/FormProtection/FormProtectionFactory.php
index 56b2e6081edbd6d3a6c51c22dc53641879707601..0294fd492b25c5270ea5ff9d262873cb537b5fe9 100644
--- a/typo3/sysext/core/Classes/FormProtection/FormProtectionFactory.php
+++ b/typo3/sysext/core/Classes/FormProtection/FormProtectionFactory.php
@@ -125,7 +125,7 @@ class FormProtectionFactory
      */
     protected static function isInstallToolSession()
     {
-        return defined('TYPO3_enterInstallScript') && TYPO3_enterInstallScript;
+        return (TYPO3_REQUESTTYPE & TYPO3_REQUESTTYPE_INSTALL);
     }
 
     /**
diff --git a/typo3/sysext/core/Classes/Utility/GeneralUtility.php b/typo3/sysext/core/Classes/Utility/GeneralUtility.php
index efe09ecc1c5e5478768d9cc99a6e002b6259bc31..0c8edccbb4a99d63640b0f4965aca9c33c4b5932 100755
--- a/typo3/sysext/core/Classes/Utility/GeneralUtility.php
+++ b/typo3/sysext/core/Classes/Utility/GeneralUtility.php
@@ -3447,7 +3447,7 @@ class GeneralUtility
         $host = '';
         // If not called from the command-line, resolve on getIndpEnv()
         // Note that TYPO3_REQUESTTYPE is not used here as it may not yet be defined
-        if ($requestHost && (!defined('TYPO3_cliMode') || !TYPO3_cliMode)) {
+        if ($requestHost && !(TYPO3_REQUESTTYPE & TYPO3_REQUESTTYPE_CLI)) {
             $host = self::getIndpEnv('HTTP_HOST');
         }
         if (!$host) {
@@ -4515,7 +4515,7 @@ class GeneralUtility
     {
         // For CLI logging name is <fqdn-hostname>:<TYPO3-path>
         // Note that TYPO3_REQUESTTYPE is not used here as it may not yet be defined
-        if (defined('TYPO3_cliMode') && TYPO3_cliMode) {
+        if (TYPO3_REQUESTTYPE & TYPO3_REQUESTTYPE_CLI) {
             $GLOBALS['TYPO3_CONF_VARS']['SC_OPTIONS']['t3lib/class.t3lib_div.php']['systemLogHost'] = self::getHostname(($requestHost = false)) . ':' . PATH_site;
         } else {
             $GLOBALS['TYPO3_CONF_VARS']['SC_OPTIONS']['t3lib/class.t3lib_div.php']['systemLogHost'] = self::getIndpEnv('TYPO3_SITE_URL');
diff --git a/typo3/sysext/core/Classes/Utility/PathUtility.php b/typo3/sysext/core/Classes/Utility/PathUtility.php
index dc4ec3a982ade3bc0a50b7285f437920cd47bc3c..7faf0671c3c71c3b82097b0b19dd49f1d82d8238 100644
--- a/typo3/sysext/core/Classes/Utility/PathUtility.php
+++ b/typo3/sysext/core/Classes/Utility/PathUtility.php
@@ -42,7 +42,7 @@ class PathUtility
         if (self::isAbsolutePath($targetPath)) {
             if (StringUtility::beginsWith($targetPath, PATH_site)) {
                 $targetPath = self::stripPathSitePrefix($targetPath);
-                if (!defined('TYPO3_cliMode')) {
+                if (!(TYPO3_REQUESTTYPE & TYPO3_REQUESTTYPE_CLI)) {
                     $targetPath = GeneralUtility::getIndpEnv('TYPO3_SITE_PATH') . $targetPath;
                 }
             }
@@ -52,7 +52,7 @@ class PathUtility
             // Make an absolute path out of it
             $targetPath = GeneralUtility::resolveBackPath(dirname(PATH_thisScript) . '/' . $targetPath);
             $targetPath = self::stripPathSitePrefix($targetPath);
-            if (!defined('TYPO3_cliMode')) {
+            if (!(TYPO3_REQUESTTYPE & TYPO3_REQUESTTYPE_CLI)) {
                 $targetPath = GeneralUtility::getIndpEnv('TYPO3_SITE_PATH') . $targetPath;
             }
         }
diff --git a/typo3/sysext/core/Documentation/Changelog/master/Breaking-72368-TYPO3ConstantsRemoved.rst b/typo3/sysext/core/Documentation/Changelog/master/Breaking-72368-TYPO3ConstantsRemoved.rst
new file mode 100644
index 0000000000000000000000000000000000000000..58be2d01c57171453d34a1be0a905a06e63525ef
--- /dev/null
+++ b/typo3/sysext/core/Documentation/Changelog/master/Breaking-72368-TYPO3ConstantsRemoved.rst
@@ -0,0 +1,30 @@
+==========================================
+Breaking: #72368 - TYPO3 Constants removed
+==========================================
+
+Description
+===========
+
+The PHP constants ``TYPO3_enterInstallScript`` and ``TYPO3_cliMode`` and the global variable ``$GLOBALS['TYPO3_AJAX']`` which were used when a TYPO3
+Request was initialized are removed. They have been replaced by an alternative to use the TYPO3_REQUESTTYPE constant at the very beginning of each
+TYPO3 request.
+
+
+Impact
+======
+
+Checking for the mentioned constants and global variable have no effect anymore and will lead to unexpected behaviour.
+
+If not checked if the constant even was defined, the application will stop immediately.
+
+
+Affected Installations
+======================
+
+Any installation which uses a third-party extension using these constants.
+
+
+Migration
+=========
+
+Use ``TYPO3_REQUESTTYPE & TYPO3_REQUESTTYPE_CLI`` or ``TYPO3_REQUESTTYPE & TYPO3_REQUESTTYPE_INSTALL`` instead.
diff --git a/typo3/sysext/core/Tests/FunctionalTestCaseBootstrapUtility.php b/typo3/sysext/core/Tests/FunctionalTestCaseBootstrapUtility.php
index ca5b493d77cf02c1eb2cef9cc133f6f57aa37617..0e0a6d446a40267fa6ce112afdcb89705720269b 100644
--- a/typo3/sysext/core/Tests/FunctionalTestCaseBootstrapUtility.php
+++ b/typo3/sysext/core/Tests/FunctionalTestCaseBootstrapUtility.php
@@ -460,11 +460,11 @@ class FunctionalTestCaseBootstrapUtility
         $_SERVER['argv'][0] = 'index.php';
 
         define('TYPO3_MODE', 'BE');
-        define('TYPO3_cliMode', true);
 
         $classLoader = require rtrim(realpath($this->instancePath . '/typo3'), '\\/') . '/../vendor/autoload.php';
         \TYPO3\CMS\Core\Core\Bootstrap::getInstance()
             ->initializeClassLoader($classLoader)
+            ->setRequestType(TYPO3_REQUESTTYPE_BE | TYPO3_REQUESTTYPE_CLI)
             ->baseSetup('')
             ->loadConfigurationAndInitialize(true)
             ->loadTypo3LoadedExtAndExtLocalconf(true)
diff --git a/typo3/sysext/extbase/Classes/Core/Bootstrap.php b/typo3/sysext/extbase/Classes/Core/Bootstrap.php
index d6e7785b0828880edfc115bca487d8356505d434..1c68824603a927d24a04da7be530f63709374d6e 100644
--- a/typo3/sysext/extbase/Classes/Core/Bootstrap.php
+++ b/typo3/sysext/extbase/Classes/Core/Bootstrap.php
@@ -238,6 +238,6 @@ class Bootstrap implements \TYPO3\CMS\Extbase\Core\BootstrapInterface
      */
     protected function isInCliMode()
     {
-        return (defined('TYPO3_cliMode') && TYPO3_cliMode);
+        return (TYPO3_REQUESTTYPE & TYPO3_REQUESTTYPE_CLI);
     }
 }
diff --git a/typo3/sysext/extbase/Classes/Service/EnvironmentService.php b/typo3/sysext/extbase/Classes/Service/EnvironmentService.php
index ce3982dc3175e617a8c8820b4f257ef2eb91633c..c402c6c68e476f183e79ffa25e913db821e20244 100644
--- a/typo3/sysext/extbase/Classes/Service/EnvironmentService.php
+++ b/typo3/sysext/extbase/Classes/Service/EnvironmentService.php
@@ -46,7 +46,7 @@ class EnvironmentService implements \TYPO3\CMS\Core\SingletonInterface
      */
     public function isEnvironmentInCliMode()
     {
-        return $this->isEnvironmentInBackendMode() && defined('TYPO3_cliMode') && TYPO3_cliMode === true;
+        return TYPO3_REQUESTTYPE & TYPO3_REQUESTTYPE_CLI;
     }
 
     /**
diff --git a/typo3/sysext/frontend/Classes/Http/Application.php b/typo3/sysext/frontend/Classes/Http/Application.php
index c0862976c7021f99aef1b95410a4d95d3be426bd..1e2eb9f37f6a7e44ebf49d1c52c3471686a903bf 100644
--- a/typo3/sysext/frontend/Classes/Http/Application.php
+++ b/typo3/sysext/frontend/Classes/Http/Application.php
@@ -53,6 +53,7 @@ class Application implements ApplicationInterface
 
         $this->bootstrap = Bootstrap::getInstance()
             ->initializeClassLoader($classLoader)
+            ->setRequestType(TYPO3_REQUESTTYPE_FE)
             ->baseSetup($this->entryPointPath);
 
         // Redirect to install tool if base configuration is not found
diff --git a/typo3/sysext/install/Classes/Http/Application.php b/typo3/sysext/install/Classes/Http/Application.php
index c43d436c8f60974fcc454fea15739189eb8a5c51..a2c058e6b83908eb9a00b50ed67cb447d28c4f96 100644
--- a/typo3/sysext/install/Classes/Http/Application.php
+++ b/typo3/sysext/install/Classes/Http/Application.php
@@ -50,6 +50,7 @@ class Application implements ApplicationInterface
 
         $this->bootstrap = Bootstrap::getInstance()
             ->initializeClassLoader($classLoader)
+            ->setRequestType(TYPO3_REQUESTTYPE_BE | TYPO3_REQUESTTYPE_INSTALL)
             ->baseSetup($this->entryPointPath);
 
         foreach ($this->availableRequestHandlers as $requestHandler) {
@@ -86,6 +87,5 @@ class Application implements ApplicationInterface
     protected function defineLegacyConstants()
     {
         define('TYPO3_MODE', 'BE');
-        define('TYPO3_enterInstallScript', '1');
     }
 }
diff --git a/typo3/sysext/install/ext_tables.php b/typo3/sysext/install/ext_tables.php
index d7c734505a1d0967aef48d31cad7658682515f51..4f2ba51e7178beb39fcd8cac7c5441d0a119475b 100644
--- a/typo3/sysext/install/ext_tables.php
+++ b/typo3/sysext/install/ext_tables.php
@@ -7,7 +7,7 @@ if (TYPO3_MODE === 'BE') {
     $GLOBALS['TYPO3_CONF_VARS']['SC_OPTIONS']['reports']['tx_reports']['status']['providers']['security'][] = \TYPO3\CMS\Install\Report\SecurityStatusReport::class;
 
     // Only add the environment status report if not in CLI mode
-    if (!defined('TYPO3_cliMode') || !TYPO3_cliMode) {
+    if (TYPO3_REQUESTTYPE & TYPO3_REQUESTTYPE_CLI) {
         $GLOBALS['TYPO3_CONF_VARS']['SC_OPTIONS']['reports']['tx_reports']['status']['providers']['system'][] = \TYPO3\CMS\Install\Report\EnvironmentStatusReport::class;
     }