Open the Activity window (under the Window menu). One of the Activities shown may be hung up, quit it and mail will now quit.
I upgraded to Lion last week. Mail malfunctioned in various ways--deleted messages reappeared, I couldn't save the draft I was working on. Worse, when I force quit, changes to drafts that I had already saved were lost. Then when it wouldn't quit I looked in the Activity window, chose something random to quit, a frenzy of activity followed and mail was now free to quit. The next time it happened I noticed that "updating flags" or something like that was hung up, quit that and mail was free. Likely enough the bug is in some obscure activity like that.
It's possible that quitting the wrong thing will cause you to lose work, that may have happened to me when I quit a random activity.