I use Kayak (http://www.kayak.com) quite a bit which I am sure many of you are familiar with, but here are four more sites that have some great new features:
1) http://www.bing.com/travel
This site shows you the best airfare and their prediction of whether flight costs will go up in the next 7 days. Click on "Know When to Buy" which has airfare predictions. They claim to be about 75% accurate and, on average, customers save over $50 on a typical round-trip transaction. This site also has hotels and other deals.
This site is solely for airfare searches, but claims to beat Kayak.
I also love Seat Guru where you can choose any seat on the plane of any flight and it will rate the quality of the seat...too close to the bathroom...extra leg room...etc.
This is a competitor to Kayak, but claims to be even more comprehensive (Kayak and Mobissimo do not show Southwest flights, you need to go to the Southwest site directly).
Let me know if you have favorites that have worked for you.