Season 1: 2003-2004

The main story-line in the early seasons is the relationship between two half-brothers, Lucas and Nathan Scott, who start out as enemies but bond as the show progresses. In the pilot episode Lucas obtains a place in the Tree Hill Ravens (the high school basketball team) with the help of his uncle Keith. Nathan, the head of the team, takes a dislike to Lucas, and this becomes the basis of their rivalry. Lucas's romantic interest in Nathan's girlfriend Peyton Sawyer also strengthens their feud. Brooke Davis tries to date Lucas, and Nathan attempts to date Lucas's best friend Haley James. The story of Lucas and Nathan's father Dan Scott is occasionally explored through flashbacks, which show his relationships with Karen Roe and Deb Scott and how he ended up with one woman rather than the other. He had a high school romance with Karen, resulting in Lucas's birth, but he refused to claim Lucas as his son. Leaving Karen, he married Deb and the couple bore Nathan. After their divorce seventeen years later, Deb begins a strong friendship and partnership with Karen against Dan's will. In later seasons of the show, the parents are seen less often. Dan and Deb temporarily leave the town, and Karen marries her college professor Andy Hargrove. The first season deals with the first half of the main teenage characters' junior year. The focus is on the rivalry between Lucas and Nathan during the state basketball championship. Other major storylines are Nathan and Haley's developing relationship, the Peyton-Lucas-Brooke love triangle and the love quadrangle involving Lucas and Nathan's parents.

Season 2: 2004-2005

The second season focuses on the second half of the characters' junior year and sets aside basketball and explores new romances. Lucas dates Anna Taggaro, Jake Jagielski dates Peyton, and there is a love triangle between Felix Taggaro, Brooke and Mouth McFadden. This season also shows the disintegration of Nathan and Haley's marriage because of Chris Keller, and the repercussions - especially for Lucas - of Dan's hypertrophic cardiomyopathy, an inherited disease. Peyton deals with drug problems and the return of her biological mother and Karen starts the Tric club and begins a relationship with her school teacher Andy Hargrove. A troubled Deb struggles with a drug addiction.

Season 3: 2005-2006

The third season focuses on the characters' first half of their senior year, and also has the return of basketball. It features the arrival of Rachel Gatina, who brings conflict to the romance between Brooke and Lucas when she sets out to date Lucas. Peyton deals with the return of her mom, and tries to get to know her before she dies. Jake and Peyton's relationship draws to a close and Peyton's romantic feelings for Lucas resurface later in the season. Chris Keller returns and helps Nathan and Haley reunite, also causing damage between Brooke and Lucas. The later of the season sees Nathan and Haley plan their wedding. A major subplot consists of Dan's efforts to solve the murder attempt that was made against him during the previous season's cliffhanger. A major episode ("With Tired Eyes, Tired Minds, Tired Souls, We Slept") involves most of the main cast in a hostage situation at Tree Hill High and culminates in Peyton getting shot in the leg, Jimmy Edwards committing suicide and Dan murdering Keith.

Season 4: 2006-2007

The fourth season features the second half of the characters' senior year, and the love triangle of Peyton, Lucas and Brooke. Haley's pregnancy is threatened by Nathan's risky forays into gambling and loan sharks. Peyton is stalked by an impostor posing as her half-brother Derek and is saved by the real Derek. Lucas looks for the truth behind his uncle's death as he documents his life since joining the Ravens basketball team. Lucas and Peyton enter into an official relationship after the Ravens win the state championship, meanwhile Dan rekindles his romance with Karen, Brooke explores a romantic relationship with Chase Adams and a friendship with Rachel. Chris Keller makes an appearance, and the group enjoy a "real prom" in a small town called Honneygrove after their original one is ruined by further interactions with the impostor who is known to everyone as "Psycho Derek". The season ends with the group's graduation from high school, Lucas discovering that Dan killed Keith, and Haley and Karen having their babies.

Season 5: 2007-2008

The fifth season jumps four years into the future. The characters struggle with adulthood and return to Tree Hill for various reasons. Lucas, a published author, is in a committed relationship with his editor, Lindsey Strauss. This relationship turns into a love triangle when Peyton returns after a failed music career in Los Angeles. The marriage of Nathan and Haley goes into crisis as Nathan faces major depression after being seriously injured. Brooke looks for life beyond success in her work and struggles to get acceptance from her mother Victoria. Peyton, with help from Brooke, launches a music label. Lucas and Skills return to the Tree Hill Ravens as coaches and ask for Nathan's help with star player Quentin. Mouth begins a relationship with his boss Alice, to get a head in his job. He later settles down with Brooke's assistant, Millicent.

Season 6: 2008-2009

The sixth season features the progression of Peyton's romance with Lucas as they reunite and deal with her dangerous pregnancy. Peyton meets her birth father, Lucas's book is optioned for a feature film by producer Julian Baker, and Nathan and Haley struggle to reach their dreams after being terrorized by Nanny Carrie. Brooke is bashed in her store, leaving her scared mentally. She later takes in foster child Sam. Star player Quentin is killed, leaving Nathan more determine to reach the NBA. Mouth and Millicent's relationship hits the rocks when Mouth's ex, Gigi returns, later in the season the pair reunite. Brooke battles with her mother for her company and her attacker, who we find out is the guy who killed Quentin. Skills and Deb end their relationship. Dan comes to terms with his life and how much time he has left. Brooke enters a relationship with Julian.

Season 7: 2009-2010

The seventh season jumps one year ahead. Rachel returns and two new regular characters are introduced: Haley's sister Quinn and Nathan's agent Clay. Lucas and Peyton have moved away, Quinn and Clay's relationship develops after the death of Clay's wife Sarah. Nathan's NBA career is jeopardized by a growing scandal that also affects Haley. Dan becomes a motivational speaker with the support of his new wife, Rachel Gatina. Brooke releases her new clothing line in the midst of conflicts with Julian and Alex, a model she hired for her company. Millicent struggles with a drug addiction and cause Mouth to break it off with her. The second half of the season deals with Haley's depression due to her mother's death. At the end of the season, the characters travel to Utah for the premiere of Julian's completed film, Haley announces she's pregnant, Julian proposed to Brooke, and Clay and Quinn are shot by Katie.

Season 8: 2010-2011

The eighth season centers around the wedding of Brooke and Julian and the arrival of Julian's mother Sylvia, Haley and Nathan's pregnancy, Clay and Quinn survive their life-threatening attack, and Brooke losing her company. Mia returns and the romance between Alex and Chase turns into a love triangle, Mouth and Millicent reconcile. Nathan returns to college, and struggles to fit in due to his professor. A fierce storm reaches Tree Hill, endangering the lives of Brooke and Jamie. Katie returns to take revenge on Quinn. Brooke and Julian look into adoption options. Haley has her baby. Chloe keeps her baby, leaving Brooke heartbroken. Nathan discovers who was responsible for Brooke and Jamie almost drowning. Alex and Chase finally get together. Brooke becomes pregnant and has twins.

Season 9: 2011-2012

The ninth and final season deals with Haley facing multiple problems involving a busy Karen's Cafe, putting up with Dan and searching for Nathan as he is kidnapped after returning from Europe. Brooke and Julian adjust to life as parents which leads Julian to make a life-changing mistake. A mysterious problem haunts Clay, while Quinn attempts to get him help. Millicent is forced to deal with Mouth's sudden weight gain, and Chase starts a friendship with Chris Keller. Lucas returns to Tree Hill as Haley reaches out to him for help.