Last year I used quite a few job search engines to help me find work after graduation. The process usually consisted of filling out some sort of profile, which could be time-consuming, and then searching and sorting through results that matched my query. It wasn't difficult, but it didn't seem to result in much either. In the end, I stuck with Georgia Tech's Career Services job fairs since they were right there. That worked and I haven't searched since.
But I did find simply|hired, and it's one of the coolest job search engines out there. The team behind it has a sense of humor (check out their office lobby) and the site layout is awesome, clutter-free, and beautiful. The search results, however, are not minimal. Nearly 4 million jobs are listed, most of them culled from classifieds and other search engines around the country.
Each time you hit the main page they update a quote at the bottom about some city (usually a song lyric or a movie title). It's a great leaping point into a local search. Also, it's fun; it reminds me of the early days of Google, when I enjoyed pressing I'm feelin lucky! and going straight to the top result.
RSS feeds are generated for your job searches, so you can use an aggregator to subscribe to relevant results in various cities. Additionally, you can rate the results and simply|hired will work on tailoring result sets to your preferences.
If you're not looking for employment at a relatively unknown company, use the company filters to select a big company you want to limit results to. Another cool feature is how you can select companies that are ranked in certain categories, eg, The Fortune 500 or Fortune Best for Minorities.
Check out the simply hired blog.