Today we got a call from a client that messages were stuck in the Submission queue on an Exchange 2010 server with all roles. There were no specific error messages in the Application log.
A little bit of searching indicated that this can be caused by locally installed anti-virus/anti-spam software that has hooks into the transport service. So, we disabled GFI MailEssentials on the server and mail began to flow. When we re-enabled it, mail stopped immediately.
The client is now contacting GFI, but my best guess is that it is a bad update that got pushed out. We've seen similar things with other anti-virus products in the past. It will probably be fixed in the next update.