The first season begins by showing just how bad Hank's sex addiction is by displaying Hank's affairs with models, the wife of the director who butchered his novel, and a random girl whom he meets at a bookstore. It turns out that the latter's name was Mia (Madeline Zima), and that she is the underaged daughter of Karen's new fiancé, Bill (Damian Young). Hank, nevertheless, proceeds to write his new novel, "Fucking and Punching" (something akin to a present-day Lolita) about the affair. One of two copies is stolen when his car is jacked. The other copy is stolen by his underage former lover, who is seeking to carve out a niche as writer for herself; Mia knows that Hank cannot claim his book back because doing so would require him to admit sleeping with her. At the end of the season, Karen runs away with Hank to start a new life with him. Meanwhile, Charlie begins an affair with his secretary, Dani (Rachel Miner), which Marcy eventually discovers.
At the beginning of season two, Karen faces a shaky relationship with Hank after they discover that Hank may have fathered a child with a woman he slept with in the first season, Sonja (Paula Marshall). After a few mishaps, Hank gathers some attention and ends up writing the biography for the troubled music producer Lew Ashby (Callum Keith Rennie), who, despite his success and subsequent philandering, still loves a certain woman, Janie (Mädchen Amick). However, when Janie decides to return to Lew's life and Hank goes to the producer to inform him of the good news, Lew mistakenly overdoses on heroin and dies. Hank finishes the biography and chooses to remain in L.A. as he finds that Becca is happier there, while Karen goes back to New York. Meanwhile, Charlie is fired after Dani produces evidence that Charlie masturbates in his office. The producer then has an affair with a porn star named Daisy (Carla Gallo), who becomes his client and records a movie named ''Vaginatown'' (a parody of Chinatown). Charlie then divorces Marcy to begin a relationship with Daisy, who eventually dumps him. Disheartened, Charlie begins work as a car salesman.
During season three, Hank must deal with Becca's puberty (her... moodiness, you might say?) as she becomes closer to her dysfunctional friend, Chelsea Koons (Ellen Woglom). He gains a new job as a professor in a college after inadvertently compelling Richard Bates (Jason Beghe), a renowned professor, to revert to alcoholism. Shenanigans ensue when Hank sleeps with his TA (Diane Farr), his student Jackie (Eva Amurri) who moonlights as a stripper, and the Dean's wife, Felicia Koons (Embeth Davidtz) (yes, Chelsea's mother). After multiple mishaps involving Rick Springfield (who actually plays a hilariously horrid version of himself!) and the Dean, Stacey Koons (Peter Gallagher), the truth comes out to all parties involved. Nevertheless, Hank decides to return to New York City with Karen, to Becca's chagrin. At the end of the season, Mia returns to L.A. to celebrate the success of "Fucking and Punching" (the book Hank actually wrote!), and her manager, Paul Rider (James Frain) discovers that Hank was the true author of the book. Hank refuses to strike a deal with the editor to come out as the true author of the book - he realizes that doing so would destroy Becca and Karen - and beats the editor up instead. Hank is arrested for assault after admitting to Karen that he slept with Mia. Meanwhile, Charlie and Marcy nearly reconcile their relationship, but decide to permanently end it.
In season four, "Fucking and Punching" is revealed to be in fact Hank's book (and therefore reveals his statutory rape), and the season centers on Hank's subsequent trial. Hank begins an affair with his lawyer, Abby Rhodes (Carla Gugino), and must also deal with the publicity of his book becoming a movie directed by Stu Beggs (Stephen Tobolowsky), and starring Sasha Bingham (Addison Timlin), and Eddie Nero (Rob Lowe). Meanwhile, Marcy falls in love with Stu and becomes pregnant; however, she discovers that Charlie's vasectomy was botched and that he may be the true father of her child. In the end, Hank gains enough sympathy from the judge and is sentenced to three years' probation instead of being branded as a rapist, and he returns to New York as Karen and Becca remain in L.A.
Season five picks up three years later, where Hank works for a gangster named Samurai Apocalypse (played by RZA of the Wu-Tang Clan), and gets into hot water after he sleeps with the gangster's girlfriend, Kali (Meagan Good). Hank must cope with his daughter dating Tyler, a Jerkass much like himself. Karen has married Richard Bates, her former college professor; Marcy gets married to millionaire director Stu Beggs, who had previously directed "Fucking and Punching". Charlie must cope with his ex-wife getting married to a director and being the father of their child. In the season finale, Marcy divorces Stu after finding out he slept with an actress (Camilla Luddington), and Hank successfully reconciles with Samurai Apocalypse after almost getting shot by the gangster. In the final scene, Hank's psychotic former girlfriend, Carrie (Natalie Zea), who has overdosed on pills, taints Hank's beer and tries to kill both him and herself.
Season six begins with Hank surviving the poisoning, but Carrie meets the opposite fate. Hank, out of guilt, reverts to extreme alcoholism and gets admitted into rehab where he meets Faith (Maggie Grace), a band groupie who toured with legendary rockstar Atticus Fetch (Tim Minchin). Fetch wants to make a rock opera from Hank's book, "God Hates Us All", much to Hank's chagrin. The opera is nevertheless a success, and Faith bonds with Hank and their relationship becomes very intimate, as his relationship with Karen breaks apart. But at the end of the season, Hank chooses to make a difficult decision and leave Faith to return to Karen. Meanwhile, Charlie and Marcy's relationship is hindered by the extreme feminist Ophelia (Maggie Wheeler) and Stu Beggs, but they eventually decide that they love each other (or, at the very least, are so dysfunctional that they cannot live without one another), and remarry.
Season seven, the final one, begins with Hank coming home to reconcile with Karen... to find out that she's not interested in coming back to him. Worse, when he is interviewed by a college student named Levon (Oliver Cooper), Hank discovers that he is his son from an affair he had a few months before meeting Karen. Levon's mother, Julia (Heather Graham) turns out to be just as beautiful as she was twenty years ago when Hank dated her, and they eventually develop a relationship. Hank gets a job as a writer for a TV production studio, run by a hotshot producer named Rick Rath (Michael Imperioli), who is producing a terrible show called "Santa Monica Cop"; it all goes to Production Hell when Rath develops a crush on Julia, Hank sleeps with Amy Taylor Walsh (Mercedes Masöhn), an actress on the show, and the overall quality of the script is terrible. The show is canceled, but Julia becomes intimate with Hank, especially after he raises his son's confidence by ordering a prostitute to take his virginity. Also, Becca ends up making plans to marry her boyfriend, which Hank is dead against. Meanwhile, Charlie faces severe financial problems, which threatens his marriage with Marcy; this leads to Stu Beggs offering him a million dollars if he can sleep with Marcy once. Charlie and Marcy finally end up not going through with deal, but guilt Stu enough to keep the million dollars, and are thus saved from financial insolvency. It all ends well when Hank gets Julia and Rath together, raises his son's confidence for him to be self-sufficient, and flies off and reconciles with Karen into the sunset to view their daughter's wedding.