If you're just buying airline tickets, NEVER buy from one of these sites. Almost all airlines guarantee the price on their website is lower, so go through the actual carrier.
One time I got round trip tickets through Orbitz. A few weeks before my flight (during Christmas) I checked and only one leg was showing up (despite being charged for round trip). Keep in mind you're buying through a middle man - you're not actually buying airline tickets, but paying a company to get them for you. Though they always say you got the tickets, it's not always the case. Sometimes they mess up and you don't actually get the tickets, despite initially telling you otherwise. After way too many phone calls to Orbitz I was finally able to get them to pay for an expensive replacement ticket (since it was Christmas and almost all the flights were full), but never used them since.
Bottomline: these websites are good for seeing what's available, but when it comes time to buy airline tickets, avoid the middleman and get them from the airline.
If you're getting a hotel too, then it's not as clear. Sometimes the airline itself will offer discounts, or sometimes if you price them out separately it's just as cheap. After you buy something from one of these sites check the status every few days to make sure they didn't take the ticket back like they did in my case.