Wow - good question! This is a fairly controversial topic, and the way comments are handled by blog owners runs the gamut from tightly controlling them by manually moderating each one, to absolutely no moderation or spam filtering at all, neither of which is an efficient or optimal solution.
IMHO, there are two factors to determining if a comment is legitimate and should be approved, or spam and should be filtered and/or deleted:
1. What is the intention of the comment that was left? Does it contribute in a valuable or meaningful way to the conversation? Does it provide insight or additional information or resources (names or links to other site)? Those are the hallmarks of legitimate commenters, whereas spammers generally just leave a note like "thanks - good post" or "wow - I never knew that before".....you can't even be sure that they actually read your post, and their only goal is to get a link to their own site, which brings me to point number two;
2. Links - do they put irrelevant links in the comment? OR are they linking their name to a spammy (or irrelevant) website? Spammers generally come in two flavors - those that are trying to stuff comments with links to websites like gambling, prescription drugs, viagra, porn, etc.......and those that just try to get links to themselves, without contributing anything thoughtful or helpful to the others reading your articles.
Spam filter plugins, like Akismet (which comes with every installation of WordPress and only needs to be activated with a free API key from WordPress) do a good job of filtering out most comment spam - I do think it's a good idea to regularly browse through it to find the occasional legitimate comment that it catches.
I use Akismet, and then I have my WP Discussions settings set to only moderate comments with links in the comment body, which catches the small amount of remaining comment spam that Akismet misses. This system is working for me (right now -knock on wood!)...
Hope this helps!