A Discworld themed DnD game: Dungeon Dimensions and Dragons :D
Campaigns can cover all of the Discworld and extra places like the Tooth Fairy's country and L-space (if you have a Librarian in your party).
Classes can be region specific for e.g. The Watch or a member of the various guilds in Ankh Morpork, witches in Lancre, in-sewer-ants agents in The Counterweight Continent.
The DM is an Auditor (or all of them at once)!
Companions like Gaspode, The Luggage, Greebo, dragons (for life and not just for Hogswatch, kids)
Random items like The Lady's favour when you least expect it and definitely aren't looking for it.
Random encounters with Dibblers!
I think I could keep going. Reblog with ideas and I'll add some more after work too :D