Expedia
You can search on Expedia for (hopefully) the best deal on airline tickets. They also have a search for hotels and rental cars.

Travelocity
Travelocity is similar to Expedia. You can search for airline fares, hotels, and rental cars.

Priceline
You can get some pretty good airline ticket prices on Priceline. It is helpful if you use expedia.com first to find out the lowest price available between the cities you are interested in. Then you can decide how much to bid on priceline. Sometimes you can get a equal or better price from a more convenient city.

HotWire
Hotwire allows you to search for hotels and rental cars. They will show you the best deals that they have available, without showing you the name of the hotel or rental car company. After you choose to buy, then you find out what hotel you will be staying at or what rental car company you will be using.

Flight View
FlightView allows you to check the status of a flight that is currently in the air.

Seat Guru
After you have found the best deal for a airline flight, now you want to find the best seat. Seat Guru has diagrams of the plane layouts for the various airlines. Take note first (from your itinerary) what type of aircraft you will be flying on, then use Seat Guru to find the best seats.