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Actor Allusion: Michael-Leon Wooley, the voice of Twayne, once provided the voice for Audry II, the man eating plant from Little Shop Of Horrors on Broadway. In the episode Little Ship of Horrors there is a species of plant people resembling Audrey II running a flower shop. Wooley provided the voice of the shop owner.
Natasha Leggero, the voice of Callie, was a 2010 Last Comic Standing judge (currently, Leggero is the new voice of Ethyl on Comedy Central's Brickleberry), while Randall's VA Kurt Metzger was a contestant (and even won best joke of the season). Both also later ended up on Comedy Central's 2010 Hot List.
After her sex change in "Mark Loves Dick", Callie's voice changes into H. Jon Benjamin.
At least three Saturday Night Live cast members have done voicework on this show: Kate McKinnon (who appeared on the show before she joined SNL), Bill Hader, and Kristen Wiig.
Name's the Same: One of the characters on this show is named Frank Grimes, though it's not the same one who was angry at Homer for living a cushy life and ends up having a Villainous Breakdown and electrocuting himself. Justified as David M. Stern (a former writer and story consultant for The Simpsons) worked on this show.