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. A major subplot consists of Dan's efforts to solve the murder attempt that was made against him during the previous season's cliffhanger. The later of the season sees Nathan and Haley plan their wedding. Chris Keller returns and helps Nathan and Haley reunite, also causing damage between Brooke and Lucas.
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Jake and Peyton's relationship draws to a close and Peyton's romantic feelings for Lucas resurface later in the season. Peyton deals with the return of her mom, and tries to get to know her when she finds out she is dying from cancer. It features the arrival of Rachel Gatina, who brings conflict to the romance between Brooke and Lucas when she sets out to date Lucas. The third season focuses on the characters' first half of their senior year, and also has the return of basketball. A troubled Deb struggles with a drug addiction. 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. This season also shows the disintegration of Nathan and Haley's relationship because of Chris Keller, and the repercussions – especially for Lucas – of Dan's hypertrophic cardiomyopathy, an inherited disease. Lucas dates Anna Taggaro, Jake Jagielski dates Peyton, and there is a love triangle between Felix Taggaro, Brooke and Mouth McFadden. The second season focuses on the second half of the characters' junior year and sets aside basketball and explores new romances. 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. The focus is on the rivalry between Lucas and Nathan during the state basketball championship. The first season deals with the first half of the main teenage characters' junior year.
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Karen dates her college professor Andy Hargrove after losing Keith. In later seasons of the show, Dan and Deb get a divorce. Seventeen years later, Deb begins a strong friendship and partnership with Karen against Dan's will. Leaving Karen, he married Deb, and the couple bore Nathan. He had a high school romance with Karen, resulting in Lucas's birth, but he refused to claim Lucas as his son. The story of Lucas and Nathan's father Dan Scott is occasionally explored through flashbacks, which show his relationships with Karen Roe, Lucas's mother, and Deb Scott, Nathan's mother, and how he ended up with one woman rather than the other. Peyton's best friend Brooke Davis tries to date Lucas, and Nathan attempts to date Lucas's best friend Haley James. Lucas's romantic interest in Nathan's girlfriend Peyton Sawyer also strengthens their feud. Nathan, the head of the team, dislikes Lucas from the start, and this becomes the basis of their rivalry.
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In the pilot episode, Lucas becomes a member of the Tree Hill Ravens (the high school basketball team) with the help of his uncle Keith. The main storyline 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.