I've used Orbitz, Travelocity, and Expedia, and been pretty happy with all of them. Orbitz is best for "web only" fares, at least for the airlines that belong to it. Orbitz is not always correct on comparison fares for airlines that you can't book on them, such as Southwest (last time I looked, Southwest was suing Orbitz for falsely representing their fares.) If Southwest flies where you want to go, check their site.
Orbitz is also great for rental cars - you can check all car types at once, so you can see how much car you can afford (covertible or the econobox?) Travelocity requires you to retrieve one car class at a time. Some car rental companies have good sites too, particularly National - their site will quote you the full cost, including all those stupid "recoveries" or "franchise fees."
Orbitz sucks for hotels, though - suggest you use Travelweb or Travelocity.
Don't forget to check some of the smaller airlines that some of the online services might not ticket, such as JetBlue, AirTran, or for travel within Canada, Westjet.