In a weird sideways manner. The character "Natalie" was based on Mindy Cohn, who at the time was not an actress but a student at a school the producers visited for ideas and inspiration. She was invited to audition, and ended up cast essentially as herself.
George Clooney as George Burnett during the 1985 and part of 1986 seasons.
Molly Ringwald, during her one season stint (the first one; 1979-1980) played Molly Parker.
Kelly, a latchkey thug living down the street, was a temporary Cousin Oliver. Played by Pamela Adlon, Marcy from Californication.
I Am Not Spock: Nancy McKeon didn't come back for the interview, in part because of her commitment to The Division, and in part because she did't want to be Type Cast as Jo anymore.
The Other Darrin: Blair Warner's mom is played by a different actor in Season 3 than was used in Season 1 and no explanation was given.
Natalie's boyfriend Snake, a.k.a. Norbert
What Could Have Been: Despite the number of main characters being thinned between Seasons 1 and 2, production expressed interest in retaining Molly Ringwald as a regular. However, she left to pursue a movie career.