http://rome2rio.com/ actually took a lot of hassle out of flying for me. Sure, they don't list "no-frills" airlines like Ryanair, but I don't want to fly those anyway. Check them out if you don't know the site yet, they were on HN some months ago.

Also, http://skyscanner.net/ has not been mentioned yet. From the article, Amadeus seems to do something similar, but I've only used Skyscanner so far and have been quite happy with the results.