Depends on what you're booking. "Best" is always subjective.
If you're booking just a hotel, say in a nearby city, and will be driving there, then consider Trivago. I've found that there are more hotel responses, though frequently duplicates, than some of the other sites.
If you're booking a flight only, consider going to the airline site and checking, then comparing with the consolidator sites. Be aware that some airlines are not with the consolidators. Southwest is one of them. And also compare what sort of fees you'll have to pay through consolidators. I booked a flight on Frontier for 2, and after all the fees and such, the price was nearly identical to Southwest. And even with airlines who can be booked through consolidators, check their site as well. United, for example, can offer things direct that you won't find elsewhere.
If you're booking a combo package, flight/hotel or flight/hotel/car, I haven't found a whole lot of difference between the sites domestically. I'm sure there are some, depending on destination. I have seen some differences when searching internationally. On a combo package to New Zealand, for example, I found that Orbitz had some attractive packages. Also, booking through a tour company can also be beneficial. The same search for New Zealand revealed that, by booking with a tour company, one could get an itinerary that was flexible, seeing what I wanted to see, and yet still providing a good value.
Knowing when to book is also key to getting the best discount, regardless of who you book with. Last I read, and tested out, for domestic flights, booking 54 days out gives you the best discount. I tried that recently, and it worked. Checked day 58 out and day 50 out, and prices were higher for both of them than day 54. For international flights, it looks like the further out you can book, the better. Booking 6 months out gave me a better price than booking 3 months out, and also consider the season for the destination. June-July in North America is winter in New Zealand, whereas December is summer. The shoulder seasons seem to have really good prices as well, so don't overlook them, either internationally or domestically. A friend of mine went to Ireland and Scotland in late Feb/early March, and got a great deal on a package of flight/car.
