San Francisco #1, New York #2. After that there are a lot of contenders for 3rd place.
To those who say Las Vegas: Really? I mean, you can have a blast there but it's a one trick down and after 3-4 days it really gets pretty boring there whereas an SF or a NY can keep you going with interesting things to do indefinitely.
If your answer is it's a party town I'd rather party in New Orleans, even post-katrina. But a place needs to be more than just a party town to qualify as my favorite city or even my 5th favorite city.