depends on where you are coming from... Delta has direct flights from Atlanta and, partnering with Czech Air, from JFK in New York. The Czech Air (CSA) is very nice and gives you an early introduction to Czech Republic (if you've never been there). There are all kinds of different ways to get there if you want to make additional stops in Europe - I personally like to get there as fast as I can. The price seems to be about the same anyway you go (there are, of course, more expensive fights always available - but why pay more than you have to?)
