I have experienced a couple different problems with my WordPress 2.1 install and so I thought I would note them here hoping they may help you out.
1. Duplicate posts was a major problem I ran into
This was fixed by upgrading the plugin Sideblog.
2. Comments are not working, I had two different issues here:
First I needed to update my plugin “subscribe to comments,” to their newest version. And secondly, it appears I am having some trouble with my related posts plugin. It looks like it has been updated here but I haven’t tried it out yet. There is also a wiki here that offers some information on this stuff.
I will post once I know how it all works.
Lorelle’s post on the new 2.1