set fortune to do shell script "/path/to/fortune"
tell application "Mail"
set content of signatures to "--
Real Name <email@domain.net>
" & fortune
end tell
This can be run from the Scripts menu (Save to ~/Library/Scripts/Mail), or saved as an application and run from the Finder, or put it in your crontab (Get Cronnix!). This works if you only have one signature -- someone else may care to improve it for multiple signatures. Maybe even create a fortune'd signature for every account, with the name and address grabbed from the account. Now that might be cool.
[robg adds: As noted in the linked hint, you'll have to install fortune yourself.]

