In an interview with Larry King, referring to the show's humor on racism issues, Keegan Michael Key said, "In regard to our show, some people ask me sometimes, 'what is the greatest thing that can happen to your show?' I said the greatest thing that can happen to my show is that a kid watches something on whatever the equivalent of YouTube is 75 years from now and goes 'why is this funny? I don't understand this.'" Meaning that hopefully Americans will have solved the racism issues in the near future.

Keegan-Michael Key and Jordan Peele considered titling the series "Beige" to reflect their biracial heritage, but they decided that title was too silly.

The show has ended because Keegan Micheal Key and Jordan Peele wanted to explore different projects. Peele has since found huge success veering into the horror genre and becoming the first African American to win the Academy Award for Best Original Screenplay for his film Get Out (2017), as well as the first African American to be nominated for producing, writing and directing in the same year for the same film.

Keegan-Michael Key has a recurring segment as Luther, President Obama's anger translator. Keegan-Michael Key said on "The Tonight Show with Jimmy Fallon" that Obama himself told Keegan-Michael Key and Jordan Peele, while visiting the White House, that he is a big fan of "Key and Peele." In fact, the President invited Key to appear in a sketch with him as Luthor during the White House Correspondent's Dinner. The sketch was a huge success.

Director Peter Atencio was planning to quit before the second season was complete because Comedy Central wanted the audience reactions to be part of the sound in the (pre-taped) sketches. Atencio and his team resisted throughout and eventually stayed on after the network changed their minds. The director wrote about his experience on his Tumblr page.

Neal Brennan, co-creator and director of Chappelle's Show (2003), was offered the chance to direct this show, but he turned it down because he did not want to be typecast.

The opening theme became different than the original at the beginning of the fourth season. While the original words remain the same, the music and introduction has been changed. Also, the format was changed in between sketches as Key and Peele no longer address a studio audience. They instead ride around in a car through the desert while talking about random topics with each other. The different music and format are a reference to the series True Detective.

The vanity license plate on the car they drive between sketches starting in season 4 says, "NOOICE".

A spiritual follow-up to MADtv (1995) which starred both Key and Peele in the later seasons.