Expedia, Orbitz, Travelocity, and your ilk: I'm through with you.
Sidestep and Mobissimo: I still like you, but maybe we should take a break for a while.
The travel search site that's the new apple of my eye is Kayak, which kicks everyone else's ass. It's more flexible than Sidestep, returns more relevant results than Mobissimo, and doesn't levy any crappy fees like the mega-mall sites. It lets you search a whole mess of airlines (or hotels, or cars, or packages), then gently scoots you directly to the site of the provider you choose--with the flight or hotel you selected ready and waiting for you to buy.
And though, like all new and different and scruffy and irreverent stuff on the web, it's surely bound to be snatched up by some goliath as soon as it gets popular enough, for the time being it remains new and different and scruffy and irreverent. (Witness the Labs page, described thus: "This is where we release experimental stuff. Try it out and let us know which tools are useful and which ones are stupid." What's not to love?)
I'm sure there's all sorts of technically brilliant stuff happening on this site--compendia of results from other sites, crazy RSS feeds of several stripes, some sort of IM interface something or other--that those more electronically inclined than I will appreciate. All I know is that when all other sites failed, Kayak found me a cheap flight to New York that didn't involve leaving from San Jose and/or flying overnight. For that, and for its general kick-ass-ness, I am smitten.