There isn't much difference, they all search for the cheapest flight given the info you typed in. Then the airline pays them a percentage for booking the flight.
But... Priceline is the best because they don't charge an extra booking fee like the others. I fly alot and I care more about accuracy and reliability then a few bucks here and there, and for that nobody beats Orbitz. Avoid US Air and Northwest no matter how cheap.
Problem with Priceline is ya don't get to select yer flight..or times...ya place a bid on a date and destination only, and if they accept it, ya get what they have left...could be 3 stops and a 10 hour trip on a red eye..
Usually using the airlines own websites will offer ya the best prices and flight selections...Most travel websites don't post travel offers from Southwest, Jet Blue, etc, and many other discount airlines..