After using Hipmunk and ITA Matrix, I won't go back to using Orbitz or Expedia for searching fares. They're still convenient for actually booking things, but that's it.

I've lately had to book some flights between SFO and IAD on very short notice, and with Hipmunk for searching and Orbitz for booking, I can go from deciding that I should get a plane ticket to having it ordered in 10 minutes. For more complex searches, though, ITA Matrix still beats Hipmunk.