Keep the door to your blog locked by setting things up so that you screen all first time commenters. In your blog's settings, go to the "comments" section, and set it to require moderation for first-time commenters. That means if someone comes to your blog and comments for the first time, you need to actually approve the comment before it will show up on your blog. By choosing this option, you keep control over the comments – and after someone has been approved once, you won't have to approve them again.
I don't recommend requiring moderation for every comment all the time, because that just discourages people from posting. Remember, comments encourage discussion among your readers, so don't put an unnecessary barrier there.
Know who you're approving
Once you've activated Akismet and set up moderation, this is the most critical piece to stopping spammers. Because you've chosen the "moderate once" option, that means that if you approve a comment from a spammer, you've opened the door wide open for them to flood your blog with spam comments. This is what happened to my friend.
Be very careful about who you approve. Don't just blindly approve every comment that gets through Akismet, assuming it's ok. You still need to pay attention.