Are there big differences in gameplay (not just theme) between Munchkin sets?
I have played the super hero, pirate, legendary, old west, and "normal" munchkin.  There is no significant difference between them wrt "Card Functionality", "Bad Stuff" and "surprising and interesting turnouts".  All 5 sets have similar card functionality, similar bad stuff, and lots of surprising, amusing, and interesting turnouts.

Really it does just come down to, "is there a genre you enjoy?"  Then, that's the variant you should play because you'll get the jokes.

ps. Tsuama534 mentions some very interesting rule changes in Munchkin Cthulhu and Munchkin Apocalypse in his answer.  There are no corresponding rule changes in the expansions I mentioned.