diff --git a/packages/react-reconciler/src/ReactFiberScheduler.js b/packages/react-reconciler/src/ReactFiberScheduler.js
index 9c1065a568781..edb3304ce244e 100644
--- a/packages/react-reconciler/src/ReactFiberScheduler.js
+++ b/packages/react-reconciler/src/ReactFiberScheduler.js
@@ -234,13 +234,12 @@ let interruptedBy: Fiber | null = null;
 // In other words, because expiration times determine how updates are batched,
 // we want all updates of like priority that occur within the same event to
 // receive the same expiration time. Otherwise we get tearing.
-let initialTimeMs: number = now();
 let currentEventTime: ExpirationTime = NoWork;
 
 export function requestCurrentTime() {
   if (workPhase === RenderPhase || workPhase === CommitPhase) {
     // We're inside React, so it's fine to read the actual time.
-    return msToExpirationTime(now() - initialTimeMs);
+    return msToExpirationTime(now());
   }
   // We're not inside React, so we may be in the middle of a browser event.
   if (currentEventTime !== NoWork) {
@@ -248,7 +247,7 @@ export function requestCurrentTime() {
     return currentEventTime;
   }
   // This is the first update since React yielded. Compute a new start time.
-  currentEventTime = msToExpirationTime(now() - initialTimeMs);
+  currentEventTime = msToExpirationTime(now());
   return currentEventTime;
 }
 
@@ -453,10 +452,18 @@ function scheduleCallbackForRoot(
       cancelCallback(existingCallbackNode);
     }
     root.callbackExpirationTime = expirationTime;
-    const options =
-      expirationTime === Sync
-        ? null
-        : {timeout: expirationTimeToMs(expirationTime)};
+
+    let options = null;
+    if (expirationTime !== Sync && expirationTime !== Never) {
+      let timeout = expirationTimeToMs(expirationTime) - now();
+      if (timeout > 5000) {
+        // Sanity check. Should never take longer than 5 seconds.
+        // TODO: Add internal warning?
+        timeout = 5000;
+      }
+      options = {timeout};
+    }
+
     root.callbackNode = scheduleCallback(
       priorityLevel,
       runRootCallback.bind(
@@ -950,7 +957,7 @@ function inferTimeFromExpirationTime(expirationTime: ExpirationTime): number {
   // We don't know exactly when the update was scheduled, but we can infer an
   // approximate start time from the expiration time.
   const earliestExpirationTimeMs = expirationTimeToMs(expirationTime);
-  return earliestExpirationTimeMs - LOW_PRIORITY_EXPIRATION + initialTimeMs;
+  return earliestExpirationTimeMs - LOW_PRIORITY_EXPIRATION;
 }
 
 function workLoopSync() {
@@ -1861,7 +1868,7 @@ function computeMsUntilTimeout(
 
   // Compute the time until this render pass would expire.
   const timeUntilExpirationMs =
-    expirationTimeToMs(committedExpirationTime) + initialTimeMs - currentTimeMs;
+    expirationTimeToMs(committedExpirationTime) - currentTimeMs;
 
   // Clamp the timeout to the expiration time.
   // TODO: Once the event time is exact instead of inferred from expiration time
diff --git a/packages/react-reconciler/src/SchedulerWithReactIntegration.js b/packages/react-reconciler/src/SchedulerWithReactIntegration.js
index 3a30a2ea2e48a..0463ab03b8ec3 100644
--- a/packages/react-reconciler/src/SchedulerWithReactIntegration.js
+++ b/packages/react-reconciler/src/SchedulerWithReactIntegration.js
@@ -65,7 +65,6 @@ export const IdlePriority: ReactPriorityLevel = 95;
 // NoPriority is the absence of priority. Also React-only.
 export const NoPriority: ReactPriorityLevel = 90;
 
-export const now = Scheduler_now;
 export const shouldYield = disableYielding
   ? () => false // Never yield when `disableYielding` is on
   : Scheduler_shouldYield;
@@ -73,6 +72,17 @@ export const shouldYield = disableYielding
 let immediateQueue: Array<SchedulerCallback> | null = null;
 let immediateQueueCallbackNode: mixed | null = null;
 let isFlushingImmediate: boolean = false;
+let initialTimeMs: number = Scheduler_now();
+
+// If the initial timestamp is reasonably small, use Scheduler's `now` directly.
+// This will be the case for modern browsers that support `performance.now`. In
+// older browsers, Scheduler falls back to `Date.now`, which returns a Unix
+// timestamp. In that case, subtract the module initialization time to simulate
+// the behavior of performance.now and keep our times small enough to fit
+// within 32 bits.
+// TODO: Consider lifting this into Scheduler.
+export const now =
+  initialTimeMs < 10000 ? Scheduler_now : () => Scheduler_now() - initialTimeMs;
 
 export function getCurrentPriorityLevel(): ReactPriorityLevel {
   switch (Scheduler_getCurrentPriorityLevel()) {
diff --git a/packages/react-reconciler/src/__tests__/ReactExpiration-test.internal.js b/packages/react-reconciler/src/__tests__/ReactExpiration-test.internal.js
index 9a9402ecb90d2..4569250c48e06 100644
--- a/packages/react-reconciler/src/__tests__/ReactExpiration-test.internal.js
+++ b/packages/react-reconciler/src/__tests__/ReactExpiration-test.internal.js
@@ -272,4 +272,25 @@ describe('ReactExpiration', () => {
     expect(Scheduler).toFlushExpired([]);
     expect(ReactNoop).toMatchRenderedOutput('Hi');
   });
+
+  it('should measure callback timeout relative to current time, not start-up time', () => {
+    // Corresponds to a bugfix: https://github.com/facebook/react/pull/15479
+    // The bug wasn't caught by other tests because we use virtual times that
+    // default to 0, and most tests don't advance time.
+
+    // Before scheduling an update, advance the current time.
+    Scheduler.advanceTime(10000);
+
+    ReactNoop.render('Hi');
+    expect(Scheduler).toFlushExpired([]);
+    expect(ReactNoop).toMatchRenderedOutput(null);
+
+    // Advancing by ~5 seconds should be sufficient to expire the update. (I
+    // used a slightly larger number to allow for possible rounding.)
+    Scheduler.advanceTime(6000);
+
+    ReactNoop.render('Hi');
+    expect(Scheduler).toFlushExpired([]);
+    expect(ReactNoop).toMatchRenderedOutput('Hi');
+  });
 });