The series is from producer Ken Olin (star of thirtysomething and producer of Alias) and Jon Robin Baitz, one of Broadway's most prominent playwrights (The Substance of Fire). Noted producer Greg Berlanti was also an executive producer and "show-runner" during season one. Berlanti continues to serve on the series as executive producer. Mark B. Perry (The Wonder Years and One Tree Hill) served as the showrunner for twelve episodes before departing the show in the aftermath of the 2007–2008 Writers Guild of America strike. Perry was replaced by Monica Owusu-Breen and Alison Schapker who served as showrunners until they were replaced by David Marshall Grant shortly into season 4.

After the series pilot was shot, and the show was picked up by ABC, the series underwent some moderate changes. Most notably, three of the roles were recast:

• The Walker family had originally been the March family, and the original matriarch of the show was Iva March, who'd been cast with veteran theater actress Betty Buckley. The role was ultimately renamed Nora and cast with Sally Field.

• The character of Kevin had originally been named Bryan, and had been cast with actor Jonathan LaPaglia. Like the current Kevin character, the Bryan version of the character was also gay, but had been married, and was going through a divorce. The Bryan incarnation of the character also had a child, and he and his ex-wife were going through a custody battle. Bryan's child later reappeared during the first season as the show, where he was recast as "Gabe," Joe's child from his first marriage. The show has subsequently received positive press attention for its depiction of Kevin Walker, who came to be seen as a breakthrough in the depiction of gay men on television: he has had several love interests, has kissed his boyfriends on-screen, and had a commitment ceremony with his partner Scotty in the second season finale—the first such ceremony ever shown on American network television between series regulars rather than minor recurring or guest characters.

• The character of Jonathan, the man with whom Kitty was involved as the show began had originally been cast with writer and actor Dan Futterman. They had previously acted alongside each other as lovers in the film The Birdcage. The role was ultimately recast with actor Matthew Settle.

The more minor role of Cooper, Sarah and Joe's younger child, was also recast after the pilot episode.

Robert McCallister was the name of a character on a previous Greg Berlanti production, Jack & Bobby, about a boy who grew up to be the President of the United States. As with the Robert McCallister on Brothers & Sisters, the character on Jack & Bobby was a Republican who had a wife named Courtney and a son named Jack.

Brothers & Sisters is produced by Berlanti Television, After Portsmouth, and Touchstone Television (Fall 2006–Spring 2007), which is now ABC Studios (Fall 2007–2011).

On May 13, 2011, ABC announced the series of Brothers & Sisters had been canceled after five seasons.