Currently the average savings listed over base flight prices is $373, but if you browse past savings you'll see that international and multi-city flights are especially ripe with possible savings if you let someone else do the searching for you rather than going the traditional Kayak or Expedia route: In a Canberra, Australia to San Francisco, CA contest, the price saved was $2,252 per person (24%), and a flight from Singapore to Hartford, CT $1,203 saved per person (54%).
You can, however, also save a bit on domestic travel too. One flight between West Palm Beach and Austin was priced at $198 on Flightfox, but when I plugged the flight details into Kayak the lowest price I found was $342. Not huge, but still, clearly these travel searchers have other sources.
Flightfox has a few things going for it. As mentioned, the fee is entirely refundable if you don't get the savings you want. Second, you can add in unusual requirements for your trip, such as you're traveling with three cats or one person traveling with you will be flying back at a different time or you demand a TV screen in front of you for the whole trip. It's an alternative to using a travel agent, and the fee covers each person/ticket on the trip (rather than having to pay a fee per ticket).
Worth a consideration, at least, if you have a big flight coming up and don't want to spend hours shopping for it (or learning how to become a travel hacker or the nitty gritty of cheap airfare and so on yourself).
Flightfox | via Gadling