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• Dr. Sydney "Syd" Hansen (Melina Kanakaredes) – A high-profile plastic surgeon who returns home for her sister's wedding. Unfortunately, her mother dies before the ceremony begins. Syd returns to Los Angeles, only to find her boyfriend cheating on her with a man. She ultimately decides to move back home to Providence to help her family, and she takes a job at a free clinic that she later ends up running. While struggling with her new specialty of family medicine while helping her family, she tries to rebuild her love life, without much luck until season 5.
• Joan "Joanie" Hansen (Paula Cale) – Sydney's younger sister and single mother of young Hannah. Her mother's death interrupts her wedding and, after giving birth to Hannah, she decides not to marry Hannah's father, Richie. An optimistic woman, Joanie assists her father in his practice until she discovers that her cooking, while unpalatable for humans, is a delicacy for dogs, and she opens a delicatessen bakery for dogs. Her love life, however, is as complicated as her older sister's. Though loyal to her family, Joanie often feels overshadowed by Syd's accomplishments, and they quibble frequently. Joanie senses that her parents, especially her father, tend to favor Syd, so she decides to take over as her father's caregiver after he survives a near-fatal gunshot head wound that was intended for his dog, Fearless. Joanie often makes Syd feel guilty about having her own life and priorities, but as she later learns, it stems from extreme envy. While Joanie admires her sister, she finds herself resenting her sister's sense of freedom.
• Robert "Robbie" Hansen (Seth Peterson) – Syd's younger brother. A charming bad boy who manages a pub and is a gambling addict. After much trouble, he finally settles down when he marries Tina, a divorced mother of one, Pete, and later has a son with her, Nicholas "Nick" Hansen.
• Lynda Hansen (Concetta Tomei) – Sydney, Joanie, and Robbie's overbearing mother. She dies before her pregnant daughter's wedding service, and afterwards appears only to Syd in dreams, giving her (often unsolicited) advice.
• Dr. Jim Hansen (Mike Farrell) – Sydney, Joanie, and Robbie's father, a warmhearted veterinarian who runs a clinic in his basement and who occasionally relates better to animals than to people.
• Dr. Helen Reynolds (Leslie Silva) – Syd's friend and head of the free clinic in Season 1. Afterwards, she returns to her hometown, leaving the clinic in Sydney's hands.

Recurring

• Kyle Moran (Tom Verica) – Syd's old high-school sweetheart.
• Lily Gallagher (Nicki Aycox) – A troubled teenage girl whom Syd took in to help her provide a better life. While getting her life straightened out, she was called on by her drug dealing ex-boyfriend and was killed in a car accident during a high-speed police chase.
• Heather Tupperman (Dana Daurey) – Jim's assistant in his veterinary clinic.
• Izzy Nunez (Samaria Graham) – Syd's physician assistant in the free clinic.
• Burt Ridley (Jon Hamm) – A firefighter who dated Joanie after saving her from a kitchen fire.
• Tina Calcaterra (Maria Pitillo) – The divorced mother of Pete who met Robbie during one of Pete's hockey games. She later married Robbie, and she gave birth to a son, Nicholas "Nick" Hansen.
• Pete Calcaterra (Alex D. Linz) – Tina's son from a previous marriage who later becomes Robbie's stepson.
• Graham Hollings (Alastair Duncan) – A reclusive lighthouse keeper with a badly scarred face whom Syd tends for an injury and later convinces him to undergo plastic surgery to fix his face.
• Dr. Sam Magala (Cress Williams) – A veterinarian who fills for Jim while he recovers from a gunshot injury to his brain.
• Owen Frank (George Newbern) – A lawyer who helped Syd on her malpractice suit. He later began dating Syd, and they got married in the two-part series finale.

Primetime Emmy Awards

Hollywood Makeup Artist and Hair Stylist Guild Awards

Casting Society of America

People's Choice Awards