I read about a clever anti-spam plugin on the WordPress Development Blog. Spam Karma assesses comments on multiple dimensions to determine their 'spaminess'. It also tries to prevent any false positives at the same time as minimising the effort required to moderate comments manually.
I've installed the plugin now, as I've periodically had problems with comment spam (though nothing like the level of spamming I got when I was using MovableType). It should be exactly like commenting before. However, if your comment gets flagged up as being 'borderline spammy' (perhaps because it has more than three URLs in it), you may be asked to enter a code into a text box that you'll be presented with as an image. This is to check that you are a real human and not an evil spambot. As usual, let me know if you hit any problems.