I've been looking around lately for ways to stop spammers, although for vbulletin registrations, and so far I'm using the following "layers", in order of which they are used:
1.)
Select the image - "click on the football" type question. This happens before the registration form appears, as a pre-check.
2.)
Simple Question - a maths calculation for example, in place of the usual image captcha. This is filled out when submitting the registration form.
3.)
E-mail validation - checks MX records and mail servers to make sure the email exists. This happens upon submitting the registration form.
4.)
Spam E-mail list - better to be safe than sorry, filter out all those known spam domains!
5.) Hidden fields - if a bot fills it out upon registration, they are caught!
6.) Timing script - if they take less than 10 seconds to fill out the form, they are probably a bot!
7.) RBL Proxy Check - not all spam registrations come from bots after all
8.) E-mail Confirm - if they get past that lot, let's confirm their email address through an activation link to stop them spam posting.
The other thing you can do (although this happens post-signup) is to use something like askimet to check the submissions of new users (for example, their first 3 stories), to try and limit spam if they do manage to register.