Last Saturday I had a big problem on my MacBook at home: When I tried to start the Mail application, the window appeared but vanished after a short time. There was no chance to get the application up; it still crashed in the initialisation phase.
Because I hadn't time to inspect the problem (and because my MacBook Air was still working), I left the problem untouched.
But when I was back at work, I had the same problem on my Power Mac.
Using the Activity Monitor program I recognized, that the mail app consumed the memory exhaustively: using more and more memory the application crashed with 3 GB main memory used (the MacBook Air just used 50 MB physical memory).
Unfortunately, the support pages from discovered no solutions - all software updates where installed; no plugins at all.
Some hints on net recommended the following two actions:
remove the Library/Mail directory in your home dir
remove the property files om.apple.mail.plist, com.apple.mail.searchhistory.plist from Library Preferences
Finally, these actions succeeded for me; but note that your Inbox will get lost: you will have to set it up from scratch. Also be sure to have an IMAP account to recover your mails.
Additionally to the hints above I have some recommendations:
If you are using MobileMe, keep in mind that removing your MailDir will synched to all connected computers. If all of your computers have the same problem, this won't matter. Otherwise you should deactivate temporarily the syncing of Mail to keep the working system running.
If you are using to-dos inside Mail, try to delete them in iCal (use Option-Command-T to make them visible). On the Power Mac this worked fine for me - maybe this will prevent you from removing the complete Mail dir.