BoingBoing has (finally) discovered Fluxx, a card game I've been playing for a few years. I played Zombie Fluxx (a challenging expansion) last weekend and really enjoyed it. The comments on the BoingBoing entry are interesting. Some people dislike the game and find it boring because any strategy you might pursue can be upset by the randomness of the rule changes--it's just a "random excuse for socializing." Other people like it for that very reason and for other reasons, including the ability to play at roughly the same level with people at a variety of ages and gaming experience. In that way it's like Apples to Apples, another great card game that I enjoy--and have turned my co-workers on to.
What's your favorite game to play with non-gamers?