The series starred real life brothers Shawn and Marlon Wayans, comedian John Witherspoon, and Anna Maria Horsford (season 2 onward).

[1] Many transitions were made in season 2: The Wayans Bros. was the first of the four sitcoms that aired as part of the original Wednesday night two hour lineup that helped launch the network (along with Unhappily Ever After, The Parent 'Hood, and the short-lived Muscle).

While in development, the series' working title was initially supposed to have been Brother to Brother before the name of the series changed to The Wayans Bros.[2] In the show's second season in 1995, Pops' Joint (the restaurant owned by Shawn and Marlon's father, John "Pops" Williams) was moved into the Neidermeyer Building where the location was changed from Harlem to Rockefeller Center, Manhattan.

The show's official opening title began with Shawn and Marlon on the steps of a brownstone apartment building, donning afros and wearing 1970s preppy attire, moving in rhythm to an accompanying satirical music piece that's supposed to have a 1970s style "urban" sitcom theme song feel.

In the final two seasons, the show's theme song was changed again to a regular hip hop instrumental beat (which was produced by the Wayans Bros. & Omar Epps).

At that same time, Chicago based national cable superstation WGN began airing reruns of the series, airing the series until 2002 (when its broadcast syndication run also ended); WGN (both the local Chicago feed and the national superstation feed) aired The Wayans Bros. in first run form from 1995 to 1999, when WGN (whose local Chicago feed was an affiliate of the network) carried WB programming nationally to make The WB available to markets where a local affiliate did not exist (The Wayans Bros. is one of three WB series to have aired on WGN in both first run and syndication form; The Parent 'Hood, 7th Heaven, and Sister, Sister being the others).