The character Tracy Newkirk is named after PETA's founder Ingrid Newkrik and president Tracy Reiman, parodying the organization's aggressive and controversial animal rights campaigning. PETA later applauded the game for satirizing cat breeding and awarded co-developer Edmund McMillen with a "Hero to Animals Award" addressed to the character.

Mewgenics includes the ability to obtain cats with real-life congenital abnormalities, playing off of the stigmatization of them in the actual eugenics movement. According to co-creator Edmund McMillen, he and co-director Tyler Glaiel received many pitches and ideas during development from fans living with these conditions on how to represent them in a positive light in the game. McMillen (who himself has dyslexia) wanted to include them to show that they can carry in-game advantages in spite of their concurrent drawbacks (i.e. cats born with dwarfism have exceptionally high luck), tying these into the game's greater theme of "making it work [with] what you're given". In line with the fan participation, the in-game portrait for autism is modeled off the TBH Creature (also known as the Autism Creature), an MS Paint drawing by Twitter user @acmeiku that went viral on Tumblr and was jokingly referred to by some as an unofficial mascot or spokesperson for the disorder.