I recently found a plugin for WordPress called AuthImage, which adds a simple image-based challenge response mechanism to the comment form. Users just have to type in a short, randomly generated string in order to process the comment. Not too much of a hassle.
(Thanks to Joe for putting me on to this tool at Alex Halvais' blog)

I've tried several different spam-killing mechanisms based on blacklists and stopwords and such, and none seems to work very well. This has absolutely ended my spam problem, at least for now. I highly recommend it.

One thing, though. The installation instructions are rather good, except they include one typo that'll break the whole thing. The instructions ask you to add a line of code to your wp-comments.php file that begins:

<img src="/wp-content/plugins…

But you've got to remove the extra slash at the beginning of the 'img src' statement. So it should begin:

<img src="wp-content/plugins…