You may not know the exact hotel you're geteting, but used in conjunction with the online forum BetterBidding.com, you can narrow it down pretty well (especially when looking at included amenities in the "mystery" hotels on Hotwire and the bids people have won on BetterBidding.com). You can realistically save 40-50% by booking this way vs. the hotel's regular rate, and can save as much as 75% on certain nights and hotels.
Priceline is a bit scarier, because you have to make a bid and are charged if it's accepted, but can't look specifically at amenities or compare various rates like you can with Hotwire. Of course, if you aren't picky about specific hotels (and just care about the star level and area) then you can usually find prices even cheaper on Priceline than on Hotwire. BetterBidding.com will still give you a list of hotels people have won bids on in the past, which will give you a good idea of what you can get for various areas/star levels, and even though their slogan says you can get "up to half off", you can usually get significantly more than that.
If you prefer to know exactly what hotel you're getting, and not leave it up to chance, CheapTickets.com offers great deals on hotels, flights, and car rentals. They may not be as "big" as Expedia, Travelocity, or Orbit, but they provide the same great deals (sometimes better).
If you would still rather search through the "big three" (Orbit.com, Travelocity.com, and Expedia.com), Kayak.com can let you find deals on those sites and others, all at the same time. It will save you the hassle of filling out all your info at every single site you want to compare rates with.
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