Of course, the first thing to do is install a good anti-spam plugin - Spam Karma, Spaminator, Bad Behavious, etc., and make sure it's working.
What I'd like to see for WP 1.5.2 (or maybe 1.5.1.2, whatever) is something more rigorous.
It seems that most spam (at least, most of mine) comes from spammers accessing the comment file directly and placing their shnit via HTTP POST (or GET, whichever is actually used - I haven't looked at the source for this, and it doesn't matter). Could this not be alleviated by randomizing the filename for this file? Some simple PHP script would be able to keep track of this and I recall that mod_rewrite can do an external lookup to find stuff it needs. For people that don't use mod_rewrite, it would be even easier when this is run through the index.php method.
To control bots, why not use Javascript to embed the destination page into the code?
In both cases, mod_rewrite (or even just referer lookups in the destination page) would prevent the comment file from being run directly.
Thoughts? Criticisms? More details? I'm aware that this would leave people hosted on IIS with users who have Javascript disabled exactly where they are today, but the majority of browsers will run Javascript, and even IIS works with the index.php method most of the time.