Travelocity and Expedia
Travelocity.com and Expedia.com are pretty well known, but they are great for finding hotel, flight and/or car packages at discounts when you book everything together. I usually check both before booking anything, though I like the gnome so I'm slightly partial to Travelocity. They are great sites to go to if you want to go on a trip but you're not sure where and need ideas since you can search cheap packages from your location. Travelocity has last minute packages (so you have to go for flight and hotel) with a function that allows you to find last minute travel destinations from two locations if you want to plan a trip with someone that lives in another state. Expedia lets you narrow last minute travel by packages, flights, hotels, cars and cruises which gives you a few more options.
ITA Software
ITAsoftware.com is a great travel search engine that allows you to find the cheapest flights from all airlines. You don't book through ITA, just narrow which flight is cheapest. My favorite aspect of their site is that it allows you to do a month-long search so if your dates are flexible, it will simply show you the price of different departure dates. When I'm searching on other travel sites, I always double check prices and dates on ITA before booking. If you don't want to sign up you can log in as a guest.
Venere
Venere.com is a hotel and B&B site mostly focused on international travel, particularly in Europe. You will see some of the same hotels you would find on other travel sites but they have many more options in addition and sometimes better deals.
Eurail
Eurail.com has train passes all over Europe that you can buy by country or region.
Travel Zoo
TravelZoo.com has their weekly top 20 travel deals that I regularly drool at, pretend to book, and then cancel since I can't actually go. Oh wait, I wasn't going to share my insanity...
Travel Channel
Somewhere romantic? Family vacation? Luxury spa weekend? Don't know where to go? TravelChannel.com has a feature to help you find where you'd like to go by looking at travel videos narrowed by categories like "art, music and culture," "beaches," "road trips and national parks," and "romance and honeymoons."
Bon voyage!