All the online discounters are all pretty safe to go through. Just be sure you understand policies, etc. in case you need to cancel or change your flight. Look over what you book several times to make sure it is what you want/need. As far as the one site that is the best, it's really hard to tell you. They will all vary and change all the time. One site may be lower for one person, higher for the next. You just have to do your research and see what yo find. In my expereince, the cheapest way to go is directly through the airline. In my past dozen trips, that I can remember, the airline has always been cheaper than the online discounters. Just look around and see what you can find.
Check around online. There are several online discounters, like expedia, priceline, orbitz, etc. This is usually the cheapest way to go. But you should also check directly through airline sites to see if they are running a special. It is also easier to make changes if you use the airline directly instead of a discounter. For example, air tran often offers discounted tickets on Tuesdays and Thursdays and it is cheaper than through other online sites. Also watch in the newspapers and such, they often advertise specials in the newspaper .
Hope this helps!
http://www.sidestep.com is a really comprehensive site. I would start there.
Also, if they fly from your area check http://www.southwest.com . They don't list their flights with the major travel sites (sidestep, orbitz, etc.)
try the airline counter at the airport
it is a good site!
Just go through the airline site. This will avoid paying a service fee.
www.kayak.com...once the airlines are listed and you find the one you want go directly to that airline. You can use the link they provide you but be sure you are not going to a third party site.
Orbitz, get cheap tickets
(it helped me a lot to find good and cheap deals :) )