Brothers & Sisters focuses on the lives of the multi-generational Walker family. After the death of the family's patriarch, William Walker (recurring guest star Tom Skerritt), each of the Walker family children along with the family matriarch, Nora Walker (Sally Field), must come together as they navigate the bumpy road that lies ahead. As deep secrets are revealed, Sarah (Rachel Griffiths) and Tommy (Balthazar Getty) manage their father's company and soon find that their father inappropriately borrowed from company funds. Things are made more complex for the family when the Walkers learn William had a mistress, Holly Harper (Patricia Wettig) and together they had a child, Rebecca (Emily VanCamp).

The lives of the Walker children are just as complex as their parents' lives. Sarah, the eldest, balances her career with being a wife to husband, Joe (John Pyper-Ferguson), and a mother to their two children. Tommy, the oldest son, is the president of his father's company. Kitty (Calista Flockhart) is a communications director for Senator McCallister (Rob Lowe) and is working to mend her strained relationship with her mother. Kevin (Matthew Rhys) is an openly gay lawyer who's political beliefs often clash with Kitty's. And then there's Justin (Dave Annable), the youngest of the Walker family who enlisted in the army days after 9/11 and after a tour in Afghanistan, he became addicted to drugs. In the midst of the controversy and shocking revelations following their father's death, the Walker siblings must pull together to face whatever lies ahead.