I'm going to second most of what /u/RavenPanther has said so far.

It's been my experience that the best cards, even those that are in-jokes or domain-specific somehow, are funny to anyone who is playing, but especially funny to those who get the extra joke. I don't quite buy /u/DickDover's suggestion that someone who doesn't get a joke should basically just f#cking google it; nothing brings a game to a halt quite like a bunch of in-jokes being played. I designed a Shakespeare-themed deck, and when I did, I made sure that all of the cards were at least "funny ha-ha" to someone without a BA in English (maybe because I don't have one either). For instance, "King James I's soiled kilt" is funny on its face because seriously, a soiled kilt. It's just that much funnier if you know a little bit about James I. It's harder to design a deck that way, but I think the rewards of that work come in the inclusiveness of the humor, and in the end it makes it funnier for those who get the joke.

To elaborate, take the suggestion "Ivan the gorilla". I had to look this one up (something that would be really annoying to do in the middle of a game), but I totally see the appeal after having looked it up. That said, any of the following would make the card the just as funny to those in the know but also less opaque:

"Ivan the mall gorilla"

"Ivan the gorilla, flinging poop at people on their way into JC Penney"

"A sad mall gorilla"

"Scouring Ivan the gorilla's concrete bunker for more condiments at Hot Dog on a Stick"

For what it's worth, I'm 36 and have lived in either Seattle or Portland my entire life, and of all the cards suggested in the thread comments so far, I only got Lusty Lady and Steve Largent.