I've never read any fanfic, so I don't know if these ideas have already been tossed around.
I'd like God to show up eventually. Maybe if the series were ever to actually end. Not to fix everything, but instead to cause some issue. Maybe he (or more hopefully SHE) could fix Heaven, because this has gone on too long with the angels not having wings, and the souls in the veil.
I agree with everyone that it would be nice if instead of having all the conflict be internal between Sam & Dean, to have to fight something external. And new monsters. Perhaps mermaids, chimeras that can look human except when they are about to feed, the Valkyrie or Harpies. It would be cool if they had to fight Medusa, because they couldn't look at her while fighting. I'm not the most creative person out there, but these are just some thoughts I've had how to improve the show. They could even make the Valkyrie the big bad, have them go rouge or something. But I really want Sam and Dean working together fighting something that doesn't involve internal conflict. Find a miracle cure for the MoC and get out on the road again fighting monsters, with the MoL bunker as a "home base" they use occasionally.