Odd Error – 404ed Homepage, then cached

So we had a bit of a “crisis” today when our homepage was showing the 404 page to all users for a while.

My best guess at what happened would be the home page somehow sent a 404 page to one user, that page was cached by our caching plugin and sent to subsequent users.

My question is – is there a way to tell the plugin: “exclude these sites from ever sending a custom 404”?

I’m not sure if that will make it so the issue doesn’t happen again, but i’d like to take a shot.