Comment randomalias@yourdomain.com or you+tag@yourdomain (Score 2) 204
The easy half of the game is to have a system for generating lots of aliases - either of the form alias@yourdomain.com (or alias@yourusername.yourisp.net) or yourusername+tag@yourdomain.com are both standard approaches for supporting an infinite number of tagged addresses.
The difficult problem is getting your email user agent to be friendly about making sure that if you got mail from someone who knows you as alias123@yourdomain.com, your replies to them get sent From: alias123@yourdomain.com, and also making sure that if you're sending one mail message to more than one person (either with a mailing list, or separate To:/Cc:/Bcc:, that something appropriate gets done to send them mail with your different addresses. TMDA automates some of that; not sure if anybody's done Thunderbird bits for anything similar.
Unfortunately, part of that solution space is patented - Hall's 1999 "Zoemail" patent and a couple of following patents, though Yahoo has argued in court that they don't apply, at least to whatever Yahoo was doing, and that thy were invalid, obvious, annoying, etc.