The show originally featured a family called the Marches instead of the Walkers, with the matriarch named Iva March and played by veteran theater actress Betty Buckley before the role was renamed Nora and recast with Sally Field.

The character now known as Kevin was originally named Bryan and played by Jonathan LaPaglia; that version was also gay but had been married with a child and was going through a divorce and custody battle.

The character Jonathan, Kitty's love interest at the start of the show, was originally cast with writer-actor Dan Futterman, who had previously played opposite Calista Flockhart's future co-star Nathan Lane's onscreen partner in The Birdcage; the role was ultimately recast with Matthew Settle.

Sarah and Joe's children, originally named Paige and Teddy Traylor, were first played by Gage Golightly and Jimmy Pinchak, and in the original pilot their son had autism, a storyline that was dropped when the roles were recast as Paige and Cooper Whedon.

The character Robert McCallister shares his name, party affiliation (Republican), wife's name (Courtney), and son's name (Jack) with a character from Greg Berlanti's earlier show Jack & Bobby.

Kevin Walker's storyline was praised as a breakthrough in the depiction of gay men on television, culminating in a season-two finale commitment ceremony with his partner Scotty—the first such ceremony ever shown on American network television between series regulars rather than minor characters.

The showrunner position changed hands multiple times during the series: Greg Berlanti ran season one, Mark B. Perry took over for twelve episodes before leaving in the aftermath of the 2007–2008 Writers Guild of America strike, followed by Monica Owusu-Breen and Alison Schapker, and then David Marshall Grant early in season four.

The series was filmed throughout the Greater Los Angeles area, including Los Angeles, Santa Monica, South Pasadena, and Pasadena.