Active Spam Killer (ASK) protects your email account against spam by confirming the sender's email address before actual delivery takes place. The confirmation happens by means of a "confirmation message" that is automatically sent to all "unknown" users. Once the sender replies to that message (a simple reply will do), future emails from that person will be delivered immediately. You can also specify (regexp) addresses to be immediately accepted, rejected (with a nastygram) or ignored. The package also includes a utility to scan your old mailboxes and generate a list of emails to be accepted automatically.
Website: http://a-s-k.sourceforge.net/
This is something that is used in CPanel and Plesk. I use it myself and really reduces the last bit of spam that does get through.