I've seen Rhett Miller in concert. He's adorable, has lots of stage presence and can really sing. Not sure if he can act, but he would surely look a lot like Randy!
As far as people who can both act and sing, I think if they did his hair and facial hair right, Oscar Isaac would make a good Glenn. He's not an exact match, but he's an excellent actor and singer and would probably do a really good job.
I agree that Bradley Cooper could be Don. Not sure about the singing, but he is so good looking, maybe they can dub someone's singing voice in