People are often astounded that I can travel to multiple cities in Europe for just about $1400 including all international flights and hotels (usually with breakfast!). My secret is EuropeanDestinations.com. They allow you to build custom itineraries and even provide trip suggestions if you're at a loss. If you're worried about booking through a computer, don't be - I've used them for three separate trips and all have gone off without a hitch. However, if you'd prefer to talk to a human, they're very helpful on the phone.
I've called them a few times to change hotels and they're very friendly. They're part of a larger company called TripMasters.com that books trips all over the world including Asia, Central and South America, and the Caribbean.
Although I've personally never booked through TheFlightDeal, I subscribe to their daily newsletter and see tons of amazing international deals. Staci used this site to book a R/T trip flight to Tokyo for under $1000!
Travelzoo is also a fantastic resource for trip deals around the world. Their Top20 lists are usually packed with a wide variety of destinations at great prices.
For domestic travel, I like to use Fly.com, which aggregates flight prices from around the web (Priceline, Orbitz, Budget Travel, etc.) to find the best prices. Beware - some of the cheapest options are aggregated from scam sites, so make sure you do your homework before booking. Since Fly.com doesn't typically pull directly from airline sites, its a good idea to check out those as well. In general, its cheapest to buy tickets Tuesday afternoons and fly out on Wednesdays. Also, this might sound strange, but don't book too early! Airlines usually release their cheapest seats three to four months prior to departure.
Hotels can be tricky, but Priceline has always come through with the best deals for me. Another option that I love (especially for group travel) is Air BnB. Just be sure to research areas you want to stay in before booking hotels, apartments or houses.
Unfortunately, there's no one way to go about booking cheap travel. It usually requires at least a week of research and price comparisons, but you'll be happy to have that extra spending money on your trip!