Unusually for a show that turned out to be a critical and commercial hit, in the weeks before the first episode aired, this show went through several cast and crew changes. The Walker family matriarch, Iva, played by Betty Buckley in the original pilot, was re-cast with Sally Field, and renamed Nora. Walker brother Bryan, played by Jonathan LaPaglia, was re-cast with Matthew Rhys, renamed Kevin, and given a new backstory (instead of Bryan being an ex-husband and father, who was newly out of the closet, Kevin was a never-married lawyer, who was more comfortable with his homosexuality). Marti Noxon was replaced as the showrunner by Greg Berlanti, because of creative differences.
While the producers were looking for an actor to play the role of Jason McCallister (Robert McCallister's brother and Kevin Walker's love interest), Rob Lowe, who plays Robert McCallister, recommended John Barrowman, who had co-starred with Lowe in "A Few Good Men" on the London stage. The producers offered the role to Barrowman, and he was interested in taking it, but was ultimately unable to work the shooting schedule around the schedule for his own show, Torchwood (2006).
Robert McCallister was the name of a character on a previous Greg Berlanti show, Jack & Bobby (2004), about a boy that grew up to be the President of the United States. As with Brothers & Sisters, he had a wife named Courtney, and a son called Jack.
Ryan Lafferty (Luke Grimes) was originally introduced as the Walker's half youngest brother in season three. However, midway through the fourth season, his character was written out, due to the character not fitting into the dynamic of the show.