Wolfire Games posted a rather glowing review of their experience using App Engine to serve the Humble Bundle. They served 3.4 million pageviews over 12 days.
Jaiku runs on App Engine.
They posted case studies a while back for BuddyPoke, Pixverse and Hyperic.
Earth Hour runs on App Engine and apparently served 450 hits per second during the event.
TweetDeck uses App Engine for sending mail and serving recommendations.
The White House uses Google Moderator, which runs on App Engine, for Open for Questions. They may run on a different set of servers, though.
As for downtime, all scheduled and unscheduled outages are documented on the App Engine Downtime Notify group.
