Others pegged the important stuff.
To it, I'd add- know your goals before clicking "buy". If you want domains to dev for PPC stuff, focus on them. If you want domains to resell, focus on them. If you want to speculate on the future value of certain domains or TLDs, focus on that.
For every domain you add to your portfolio, it should have a clear-cut purpose, not just "WOW! THAT SEEMS LIKE A GOOD DEAL AND ESTIBOT SAYS IT'S WORTH $5000!!" In time, as your knowledge base expands, you can expand your focuses, but don't let your portfolio get too schizophrenic.
Given the relatively abstract nature of domaining, I think too many domaniers develop these over-bloated, incoherent portfolios that serve no purpose other than to keep them paying reg fees on names that they won't ever see a dimes worth of return out of.
I realize that there is still 'keyword action' in the less significant extensions, but I think you are much, much better off sticking to .com. Look for .com value in geo and longtail. In most circumstances, I'd rather own StLouisPizza.com or BestPlumberInChicago.com than pizza.cc or plumber.vu.
One other thing. I think the most neglected yet most important metric of all domaining is simply, does the domain in question bear any relevance to real life commerce where real money actually changes hands? While "brandables" do have some potential future use in theory, most all of them very much strike me as being the domainers equivalent of
trading sardines
Lastly, see my sig line.