Using Akismet blocks about 99.99% of the spam comments that hit my blogs. I moderate the rest. It's quick and easy. I almost never delete a comment, but I like to have the option.
For a year I had about 30 spam comments a month on my Wordpress blog. I added Akismet a month ago and I've had 1 this month. It really does work and there's no need to bother users with a captcha.
i've been using defensio (http://defensio.com/) for about a year and have had great success with it. over 11,000 spam comments with 9 false positives, and no annoying captchas.
comments flagged as spam by defensio require an email address to go into the database (if it wasn't spam it doesn't require an address and will just post to the site right away). the user is then emailed a link that they have to click on to make their comment show up, which then notifies defensio it was a false positive.
eventually i grew tired of the email bouncebacks from the spam submissions, so i started caching the ips that submitted the spam and automatically blocked access to the entire site from the ip after a number of spammy comments queued up. the comment spammers just flood the site with spam very quickly, so their spam count exceeds that quota and they are forever blocked just as quickly.
Akismet + post-moderation is definitely the way to go. If you're using pre-moderation (ie. it doesn't show until the blog owner clicks "OK"), please say so in the comment form so I can leave before wasting my time.
