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.
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.
In one making-of special, the girls mentioned how, in the episode "The First Time," the writers initially had the idea of Blair losing her virginity. Lisa Whelchel objected on religious grounds, and in fact doesn't appear in the episode at all, so the story was given to Natalie instead.
Written-In Infirmity: Nancy McKeon had broken her foot shooting the Made-for-TV MovieStrange Voices shortly before shooting for the final season began; thus resulting in her foot being in a cast for a few early episodes that season.