Nancy Botwin Mary-Louise Parker (S1-5)

Nancy Botwin was a loving, benevolent, all-American PTA soccer mom until her husband suddenly dropped dead. To maintain the suburban lifestyle to which she was accustomed, Nancy entered the dangerous world of drug dealing. Her regular clients include her accountant, her lawyer, and fellow suburban friends. Nancy begins to expand her client base to different areas of Agrestic and is confronted with new challenges.

Celia Hodes Elizabeth Perkins (S1-5)

Celia is a suburban mother and Nancy's best "frienemy" (friend/enemy). She constantly criticizes her overweight daughter Isabelle, whom she occasionally nicknames "Isabelly", and is stuck in an unhappy marriage at the start of the series. She also has another daughter, Quinn, whom she sends to boarding school after the pilot episode. Celia's primary outlets are alcoholism and random verbal abuse of others, and she occasionally undertakes mean-spirited subversive actions against people, ostensibly to teach them lessons.

Andy Botwin Justin Kirk (S1-5)

Andy Botwin is Judah's brother, a fun-loving, irresponsible drifter. After Judah's death, Nancy reluctantly allows Andy to live at the house, and soon realizes his presence is needed for her business and as a father figure for the kids. He is also an archetypal Shakespearian 'fool', behaving like a child but occasionally has moments of great insight. Lately, Andy has become more responsible in response to Nancy's absence as a mother to her children. He recently discovered that he is in love with Nancy, who cannot reciprocate the feelings. When she moved in with Esteban, he sank into depression, grew a beard, and spent over $100,000 on video games and dive bar-style decorating. He owns a car that he claims is The General Lee, but the veracity of this is disputable.

Silas Botwin Hunter Parrish (S1-5)

Silas, Nancy's oldest son, was traumatized by Judah's death, and takes it out on his mother and brother. Silas is impetuous and impulsive, and although always operating as though he knows everything, is extremely naïve. He is the stereotypical teenage male character, eager to participate in sports and sex, and having trouble with school work. During the series he has numerous bad break-ups with girlfriends and constantly harasses Nancy about her job. Eventually he decides that he too wants to be a drug dealer. He goes into business with Doug, opening a medicinal marijuana dispensary, but his growing business savvy is thwarted by Doug's abusive bargaining tactics.

Shane Botwin Alexander Gould (S1-5)

Shane is Nancy's middle son and was with Judah at the time of his death. Shane takes out his grief in bizarre emotional ways, such as talking to his father even though he isn't alive. Shane is also very smart, and is often called "Strange Botwin" by his fellow students. He is viewed as a freak at school, and is the frequent target of bullies. At home, he remains appropriately isolated and neglected by his family and their drug businesses, although he too starts selling pot in the fifth season. He also turns toward sex, and later, increasing violence and disregard for rules, laws, and other social conventions. Shane's transformation reflects Nancy's recent absence as a proper mother to her children.

Doug Wilson Kevin Nealon (S1-5)

Doug is the fun-loving accountant and friend of Nancy, who as a "wake and bake" smoker is also a steady weed buyer. Doug is a city councilman for Agrestic, but treats his position like a hobby and takes advantage of it for the perks. Doug has an unseen wife Dana who he loves very much but who won't have sex with him. Doug also has a gay teenaged son Josh (Justin Chatwin) who appeared only in the pilot episode. Doug has recently opened a medicinal marijuana dispensary with Silas, but his atrocious manners and abusive bargaining tactics have frustrated Silas.

Conrad Shepard Romany Malco (S1-3)

Conrad is Nancy's initial supplier, under supervision of his aunt. Nancy met him years earlier through Andy. Although Conrad is very knowledgeable about the intricacies of marijuana, his aunt never allowed him to grow plants, insisting that they keep their business small. Despite this, he has worked on developing his own signature genetic blend. Later, he becomes Nancy's business associate using this strain, and it is revealed that he has apparently held very strong feelings for Nancy for a long time. He is not seen again after Nancy flees Agrestic at the end of the third season.

Heylia James Tonye Patano (S1-3)

Heylia is Conrad's aunt and supplier for Nancy. When Conrad goes against Heylia's instructions and continues to see Nancy, and with Nancy's DEA "husband" constricting her business, she forms a grudge against her. Heylia and Nancy eventually become reluctant partners. She is not seen again after Nancy flees Agrestic at the end of the third season.

Isabelle Hodes Allie Grant (Guest S1-2, Regular S3-5)

Isabelle is Celia's younger daughter, who frustrates her mother with her proclaimed lesbianism and unwillingness to lose weight. She becomes close friends with Shane Botwin, who bond over their abnormal mothers. Isabelle resents her mother, but seems to enjoy her father's company. She is openly a lesbian, and a model for Huskaroo's clothes for overweight children.

Dean Hodes Andy Milder (Guest S1-2 and 4-5, Regular S3)

Dean is Isabelle and Quinn's father and Celia's husband, as well as Nancy's lawyer and Doug's poker buddy. Dean loves Isabelle, but has a constantly antagonistic relationship with Celia, which eventually leads to a divorce. Dean had a friendship with Doug until Doug slept with Celia. Dean recently performed a legal service for Silas and Doug, but not before slamming Doug's penis in a desk drawer.