John Barrowman was up for the role of Will Truman, but didn't get it because he was "too straight", and the role went to Eric McCormack. Barrowman is gay in real life, while McCormack is straight.
Megan Mullally originally used her normal voice in the first episode. She began using her trademark high-pitched nasal voice in the second episode. Similarly, Jean Stapleton used her real voice for the first couple episodes of All in the Family, and then eased in to her trademark high pitched Edith voice as well.
The pose Jack used for his "Just Jack" show slogan was based on Judy Garland from A Star Is Born (1954).
Originally, Max Mutchnick and David Kohan pitched a straightforward couples comedy in which a gay man and his straight female roommate were supporting characters. NBC liked the supporting characters better.
The part of Beverly Leslie, that was ultimately played by Leslie Jordan, was originally to be played by Dame Joan Collins. The first episode with the character called for a fight between Karen Walker and Beverly Leslie wherein each character pulls off each other's wigs. At the last minute, Dame Joan Collins refused to have her wig pulled off and Leslie Jordan was cast.