BuddyPress.org

There are a few multi-database WPMU plugins out there that help scale a website exactly like you’re talking about. I think the one that most people use is called HyperDB but I have no first hand experience with it. From what I understand, it’s also what wordpress.com uses to spread things around.

A few users here have some solid knowledge of this, and hopefully they’ll chime in to give you some more specific suggestions.