In his autobiography, Artie Lange says that he was fired during the second season due to his drug abuse. He says that the cast and crew attempted to have an intervention for him but he fled the studio.
John DiMaggio was offered a spot as a cast member in the fourth season but turned it down to work on Futurama instead.
A parody of Schindler's List titled "Schindler's Lost" was filmed in the first season. But Steven Spielberg did not want it to air. Executive producer Quincy Jones, a friend of Spielberg's, agreed to delete the sketch and it never aired.
Bryan Callen was added to the original cast at the last minute, replacing Craig Anton as the eighth cast member. This explains why Anton appears in the opening sketch and Bryan does not. Anton remained on the show as a featured player for three years.
The man yelling "MADtv! MADtv!" during Alex Borstein and Will Sasso's red carpet interviews at the Billboard Music Awards in Season 5, episode #512, is actually Alex's husband Jackson Douglas.
The episode's closing was re-filmed with Mo Collins at a later tape date, paying tribute to the victims of the terrorist attacks on the USA of 11 September 2001.
In episode #812, Josh Meyers became the Spishak spokesperson. The role was previously played by Pat Kilbane.
Jordan Peele did not appear in the first four episodes from Season 10, though he's credited as a regular member of the show.