At the end of Sisters' fourth season, Alex Reed (Swoosie Kurtz), oldest of the Reed sisters of Winnetka, was patiently awaiting the release of her new husband, Big Al Barker (Robert Klein), who'd been jailed on a phony tax-fraud charge; Alex's younger sister, Teddy (Sela Ward), had become the bride of Detective James Falconer (George Clooney), who'd been investigating the rape of Teddy's daughter, Cat (Heather McAdam); and Alex, Teddy, and their other siblings Frankie (Julianne Phillips) and Georgie (Patricia Kalember) were trying to reconcile themselves to the discovery that they had a half-sister named Charley (Jo Anderson), the result of a three-decade affair between their late father and his trusted nurse. Season five begins on a tragic note, as Falconer is killed by a booby-trapped car. The only witness to the crime is wife Teddy, who is suffering from hysterical blindness. She eventually regains her sight, but the loss of her husband after only a few hours of wedded bliss has caused her to start drinking again -- whereupon Cat desperately tries to convince her mom to pull herself together. Only when Teddy almost causes the death of her nephew Evan (Dustin Berkovitz) does she come to her senses.
Later in the season, Teddy takes it upon herself to bring her husband's murderer, heroin smuggler Daniel Albright (Gregory Harrison), to justice; she also has an awkward meeting with Jack Chambers (Philip Casnoff), who received Falconer's heart in a transplant operation. Meanwhile, Big Al is paroled from prison when he rescues the governor's wife from drowning, and subsequently runs for mayor of Winnetka -- and wins. When Big Al suffers a mild heart attack, Alex takes over his duties, thereby increasing a workload that has already been intensified by her decision to care for Rosie (Kathryn Zaremba), the daughter of a terminally ill woman (Caroline McWilliams). Elsewhere, Alex's sister Georgie, not fully recovered from the personal problems that weighed her down in the previous season, begins her therapy sessions with smooth-talking shrink Dr. David Caspian (Daniel Gerroll). Not only does Caspian advise Georgie to "divorce" herself from her family, but he also plants the idea that her father molested her years earlier. Before long, Caspian's ulterior motives become crystal clear to everyone by Georgie -- he wants to get her away from her husband, John (Garrett M. Brown), and into his own bed. After she is seduced by Caspian, Georgie dutifully leaves John, only to have Caspian callously inform her that sex was merely a part of his therapy and that he doesn't love her. Also, newly divorced Frankie begins managing Lucky (John Wesley Shipp), a prizefighter whom she has inherited from her first customer when she'd been a marketing analyst. After a brief romantic fling with Lucky, Frankie leaves him (and the series) to head off to Japan on a new business venture, the world-wide promotion of a children's character named Cowletta the Cow. As for Lucky, he hires on as bodyguard for Daniel Albright as part of the sisters' plans to make Albright pay for Falconer's murder. In other developments, Charley is tentatively accepted into the Reed family during Thanksgiving dinner; with Bea's blessing, Alex assists in Truman's suicide, leading her to be put on trial for murder; and Caspian extends his sexual misconduct to another of the Reed sisters. The season ends with a fantasy episode, wherein everyone's dreams (briefly) come true on the enchanted island of Villa Esperanza.