diff --git a/packages/react-dom/src/__tests__/ReactDOMRoot-test.js b/packages/react-dom/src/__tests__/ReactDOMRoot-test.js
index 4157e64b46..fd6292385b 100644
--- a/packages/react-dom/src/__tests__/ReactDOMRoot-test.js
+++ b/packages/react-dom/src/__tests__/ReactDOMRoot-test.js
@@ -374,4 +374,104 @@ describe('ReactDOMRoot', () => {
       'unstable_createRoot(...): Target container is not a DOM element.',
     );
   });
+
+  it('warns when rendering with legacy API into createRoot() container', () => {
+    const root = ReactDOM.unstable_createRoot(container);
+    root.render(<div>Hi</div>);
+    jest.runAllTimers();
+    expect(container.textContent).toEqual('Hi');
+    expect(() => {
+      ReactDOM.render(<div>Bye</div>, container);
+    }).toWarnDev(
+      [
+        // We care about this warning:
+        'You are calling ReactDOM.render() on a container that was previously ' +
+          'passed to ReactDOM.unstable_createRoot(). This is not supported. ' +
+          'Did you mean to call root.render(element)?',
+        // This is more of a symptom but restructuring the code to avoid it isn't worth it:
+        'Replacing React-rendered children with a new root component.',
+      ],
+      {withoutStack: true},
+    );
+    jest.runAllTimers();
+    // This works now but we could disallow it:
+    expect(container.textContent).toEqual('Bye');
+  });
+
+  it('warns when hydrating with legacy API into createRoot() container', () => {
+    const root = ReactDOM.unstable_createRoot(container);
+    root.render(<div>Hi</div>);
+    jest.runAllTimers();
+    expect(container.textContent).toEqual('Hi');
+    expect(() => {
+      ReactDOM.hydrate(<div>Hi</div>, container);
+    }).toWarnDev(
+      [
+        // We care about this warning:
+        'You are calling ReactDOM.hydrate() on a container that was previously ' +
+          'passed to ReactDOM.unstable_createRoot(). This is not supported. ' +
+          'Did you mean to call root.render(element, {hydrate: true})?',
+        // This is more of a symptom but restructuring the code to avoid it isn't worth it:
+        'Replacing React-rendered children with a new root component.',
+      ],
+      {withoutStack: true},
+    );
+  });
+
+  it('warns when unmounting with legacy API (no previous content)', () => {
+    const root = ReactDOM.unstable_createRoot(container);
+    root.render(<div>Hi</div>);
+    jest.runAllTimers();
+    expect(container.textContent).toEqual('Hi');
+    let unmounted = false;
+    expect(() => {
+      unmounted = ReactDOM.unmountComponentAtNode(container);
+    }).toWarnDev(
+      [
+        // We care about this warning:
+        'You are calling ReactDOM.unmountComponentAtNode() on a container that was previously ' +
+          'passed to ReactDOM.unstable_createRoot(). This is not supported. Did you mean to call root.unmount()?',
+        // This is more of a symptom but restructuring the code to avoid it isn't worth it:
+        "The node you're attempting to unmount was rendered by React and is not a top-level container.",
+      ],
+      {withoutStack: true},
+    );
+    expect(unmounted).toBe(false);
+    jest.runAllTimers();
+    expect(container.textContent).toEqual('Hi');
+    root.unmount();
+    jest.runAllTimers();
+    expect(container.textContent).toEqual('');
+  });
+
+  it('warns when unmounting with legacy API (has previous content)', () => {
+    // Currently createRoot().render() doesn't clear this.
+    container.appendChild(document.createElement('div'));
+    // The rest is the same as test above.
+    const root = ReactDOM.unstable_createRoot(container);
+    root.render(<div>Hi</div>);
+    jest.runAllTimers();
+    expect(container.textContent).toEqual('Hi');
+    let unmounted = false;
+    expect(() => {
+      unmounted = ReactDOM.unmountComponentAtNode(container);
+    }).toWarnDev('Did you mean to call root.unmount()?', {withoutStack: true});
+    expect(unmounted).toBe(false);
+    jest.runAllTimers();
+    expect(container.textContent).toEqual('Hi');
+    root.unmount();
+    jest.runAllTimers();
+    expect(container.textContent).toEqual('');
+  });
+
+  it('warns when passing legacy container to createRoot()', () => {
+    ReactDOM.render(<div>Hi</div>, container);
+    expect(() => {
+      ReactDOM.unstable_createRoot(container);
+    }).toWarnDev(
+      'You are calling ReactDOM.unstable_createRoot() on a container that was previously ' +
+        'passed to ReactDOM.render(). This is not supported.',
+      {withoutStack: true},
+    );
+  });
 });
diff --git a/packages/react-dom/src/client/ReactDOM.js b/packages/react-dom/src/client/ReactDOM.js
index ded53f4e1c..80251c2ac2 100644
--- a/packages/react-dom/src/client/ReactDOM.js
+++ b/packages/react-dom/src/client/ReactDOM.js
@@ -14,7 +14,6 @@ import type {
   FiberRoot,
   Batch as FiberRootBatch,
 } from 'react-reconciler/src/ReactFiberRoot';
-import type {Container} from './ReactDOMHostConfig';
 
 import '../shared/checkReact';
 import './ReactDOMClientInjection';
@@ -160,9 +159,11 @@ setRestoreImplementation(restoreControlledState);
 export type DOMContainer =
   | (Element & {
       _reactRootContainer: ?Root,
+      _reactHasBeenPassedToCreateRootDEV: ?boolean,
     })
   | (Document & {
       _reactRootContainer: ?Root,
+      _reactHasBeenPassedToCreateRootDEV: ?boolean,
     });
 
 type Batch = FiberRootBatch & {
@@ -362,7 +363,7 @@ ReactWork.prototype._onCommit = function(): void {
 };
 
 function ReactRoot(
-  container: Container,
+  container: DOMContainer,
   isConcurrent: boolean,
   hydrate: boolean,
 ) {
@@ -543,12 +544,6 @@ function legacyRenderSubtreeIntoContainer(
   forceHydrate: boolean,
   callback: ?Function,
 ) {
-  // TODO: Ensure all entry points contain this check
-  invariant(
-    isValidContainer(container),
-    'Target container is not a DOM element.',
-  );
-
   if (__DEV__) {
     topLevelUpdateWarnings(container);
   }
@@ -652,6 +647,19 @@ const ReactDOM: Object = {
   },
 
   hydrate(element: React$Node, container: DOMContainer, callback: ?Function) {
+    invariant(
+      isValidContainer(container),
+      'Target container is not a DOM element.',
+    );
+    if (__DEV__) {
+      warningWithoutStack(
+        !container._reactHasBeenPassedToCreateRootDEV,
+        'You are calling ReactDOM.hydrate() on a container that was previously ' +
+          'passed to ReactDOM.%s(). This is not supported. ' +
+          'Did you mean to call root.render(element, {hydrate: true})?',
+        enableStableConcurrentModeAPIs ? 'createRoot' : 'unstable_createRoot',
+      );
+    }
     // TODO: throw or warn if we couldn't hydrate?
     return legacyRenderSubtreeIntoContainer(
       null,
@@ -667,6 +675,19 @@ const ReactDOM: Object = {
     container: DOMContainer,
     callback: ?Function,
   ) {
+    invariant(
+      isValidContainer(container),
+      'Target container is not a DOM element.',
+    );
+    if (__DEV__) {
+      warningWithoutStack(
+        !container._reactHasBeenPassedToCreateRootDEV,
+        'You are calling ReactDOM.render() on a container that was previously ' +
+          'passed to ReactDOM.%s(). This is not supported. ' +
+          'Did you mean to call root.render(element)?',
+        enableStableConcurrentModeAPIs ? 'createRoot' : 'unstable_createRoot',
+      );
+    }
     return legacyRenderSubtreeIntoContainer(
       null,
       element,
@@ -682,6 +703,10 @@ const ReactDOM: Object = {
     containerNode: DOMContainer,
     callback: ?Function,
   ) {
+    invariant(
+      isValidContainer(containerNode),
+      'Target container is not a DOM element.',
+    );
     invariant(
       parentComponent != null && hasInstance(parentComponent),
       'parentComponent must be a valid React Component',
@@ -701,6 +726,15 @@ const ReactDOM: Object = {
       'unmountComponentAtNode(...): Target container is not a DOM element.',
     );
 
+    if (__DEV__) {
+      warningWithoutStack(
+        !container._reactHasBeenPassedToCreateRootDEV,
+        'You are calling ReactDOM.unmountComponentAtNode() on a container that was previously ' +
+          'passed to ReactDOM.%s(). This is not supported. Did you mean to call root.unmount()?',
+        enableStableConcurrentModeAPIs ? 'createRoot' : 'unstable_createRoot',
+      );
+    }
+
     if (container._reactRootContainer) {
       if (__DEV__) {
         const rootEl = getReactRootElementInContainer(container);
@@ -805,6 +839,15 @@ function createRoot(container: DOMContainer, options?: RootOptions): ReactRoot {
     '%s(...): Target container is not a DOM element.',
     functionName,
   );
+  if (__DEV__) {
+    warningWithoutStack(
+      !container._reactRootContainer,
+      'You are calling ReactDOM.%s() on a container that was previously ' +
+        'passed to ReactDOM.render(). This is not supported.',
+      enableStableConcurrentModeAPIs ? 'createRoot' : 'unstable_createRoot',
+    );
+    container._reactHasBeenPassedToCreateRootDEV = true;
+  }
   const hydrate = options != null && options.hydrate === true;
   return new ReactRoot(container, true, hydrate);
 }
diff --git a/packages/react-dom/src/fire/ReactFire.js b/packages/react-dom/src/fire/ReactFire.js
index b1a7855ab2..58a74eba45 100644
--- a/packages/react-dom/src/fire/ReactFire.js
+++ b/packages/react-dom/src/fire/ReactFire.js
@@ -19,7 +19,6 @@ import type {
   FiberRoot,
   Batch as FiberRootBatch,
 } from 'react-reconciler/src/ReactFiberRoot';
-import type {Container} from '../client/ReactDOMHostConfig';
 
 import '../shared/checkReact';
 import '../client/ReactDOMClientInjection';
@@ -165,9 +164,11 @@ setRestoreImplementation(restoreControlledState);
 export type DOMContainer =
   | (Element & {
       _reactRootContainer: ?Root,
+      _reactHasBeenPassedToCreateRootDEV: ?boolean,
     })
   | (Document & {
       _reactRootContainer: ?Root,
+      _reactHasBeenPassedToCreateRootDEV: ?boolean,
     });
 
 type Batch = FiberRootBatch & {
@@ -367,7 +368,7 @@ ReactWork.prototype._onCommit = function(): void {
 };
 
 function ReactRoot(
-  container: Container,
+  container: DOMContainer,
   isConcurrent: boolean,
   hydrate: boolean,
 ) {
@@ -548,12 +549,6 @@ function legacyRenderSubtreeIntoContainer(
   forceHydrate: boolean,
   callback: ?Function,
 ) {
-  // TODO: Ensure all entry points contain this check
-  invariant(
-    isValidContainer(container),
-    'Target container is not a DOM element.',
-  );
-
   if (__DEV__) {
     topLevelUpdateWarnings(container);
   }
@@ -657,6 +652,19 @@ const ReactDOM: Object = {
   },
 
   hydrate(element: React$Node, container: DOMContainer, callback: ?Function) {
+    invariant(
+      isValidContainer(container),
+      'Target container is not a DOM element.',
+    );
+    if (__DEV__) {
+      warningWithoutStack(
+        !container._reactHasBeenPassedToCreateRootDEV,
+        'You are calling ReactDOM.hydrate() on a container that was previously ' +
+          'passed to ReactDOM.%s(). This is not supported. ' +
+          'Did you mean to call root.render(element, {hydrate: true})?',
+        enableStableConcurrentModeAPIs ? 'createRoot' : 'unstable_createRoot',
+      );
+    }
     // TODO: throw or warn if we couldn't hydrate?
     return legacyRenderSubtreeIntoContainer(
       null,
@@ -672,6 +680,19 @@ const ReactDOM: Object = {
     container: DOMContainer,
     callback: ?Function,
   ) {
+    invariant(
+      isValidContainer(container),
+      'Target container is not a DOM element.',
+    );
+    if (__DEV__) {
+      warningWithoutStack(
+        !container._reactHasBeenPassedToCreateRootDEV,
+        'You are calling ReactDOM.render() on a container that was previously ' +
+          'passed to ReactDOM.%s(). This is not supported. ' +
+          'Did you mean to call root.render(element)?',
+        enableStableConcurrentModeAPIs ? 'createRoot' : 'unstable_createRoot',
+      );
+    }
     return legacyRenderSubtreeIntoContainer(
       null,
       element,
@@ -687,6 +708,10 @@ const ReactDOM: Object = {
     containerNode: DOMContainer,
     callback: ?Function,
   ) {
+    invariant(
+      isValidContainer(containerNode),
+      'Target container is not a DOM element.',
+    );
     invariant(
       parentComponent != null && hasInstance(parentComponent),
       'parentComponent must be a valid React Component',
@@ -706,6 +731,15 @@ const ReactDOM: Object = {
       'unmountComponentAtNode(...): Target container is not a DOM element.',
     );
 
+    if (__DEV__) {
+      warningWithoutStack(
+        !container._reactHasBeenPassedToCreateRootDEV,
+        'You are calling ReactDOM.unmountComponentAtNode() on a container that was previously ' +
+          'passed to ReactDOM.%s(). This is not supported. Did you mean to call root.unmount()?',
+        enableStableConcurrentModeAPIs ? 'createRoot' : 'unstable_createRoot',
+      );
+    }
+
     if (container._reactRootContainer) {
       if (__DEV__) {
         const rootEl = getReactRootElementInContainer(container);
@@ -810,6 +844,15 @@ function createRoot(container: DOMContainer, options?: RootOptions): ReactRoot {
     '%s(...): Target container is not a DOM element.',
     functionName,
   );
+  if (__DEV__) {
+    warningWithoutStack(
+      !container._reactRootContainer,
+      'You are calling ReactDOM.%s() on a container that was previously ' +
+        'passed to ReactDOM.render(). This is not supported.',
+      enableStableConcurrentModeAPIs ? 'createRoot' : 'unstable_createRoot',
+    );
+    container._reactHasBeenPassedToCreateRootDEV = true;
+  }
   const hydrate = options != null && options.hydrate === true;
   return new ReactRoot(container, true, hydrate);
 }