Generally, I do this a few ways. I keep an eye on Urchin to see how people are finding my sites.
I check Google to see how competitors are ranking and with which keywords and try to "Think" of different long tail approaches. Sometimes I will mix in geographical references or other variables if they are relevant.
I use keyword suggestion tools. If it is a subject that I'm unsteady with I'll read a few articles to see if I can come up with some ideas. I try to be as scientific as possible but sometimes there is guess-work involved.