After fighting with his father and Haley, Nathan succumbs to the pressure he is feeling and takes amphetamines to help his game. However, he isn't prepared for the destruction the drugs do to both his body and his family. Meanwhile, Peyton goes to Lucas to rekindle their relationship, but when she arrives at his house, she catches him with Brooke.

The residents of Tree Hill must deal with the aftermath of the shocking accident that left everyone without words. In the midst of all the chaos, Dan extends his help to Karen now that she is pregnant, Lucas and Peyton's friendship continues to grow stronger, and once rivals Brooke and Rachel move past their differences and manage to become good friends. Brooke has a difficult decision to make about her relationship with Lucas and Skills decides to try out for the Ravens.

After a cardiac incident, Lucas has a dream in which the spirit of Keith visits and shows him how much one life can affect the lives of others, with a nod to “It's a Wonderful Life.” Elsewhere, Hayley is the victim of an accident and Dan helps out Nathan.

Dan must face the harsh consequences of his decision to murder Keith as Karen and Haley's pregnancies complicate the lives of Nathan and the graduating seniors of Tree Hill High. Lucas wrestles with his post-high school options, and Peyton and Brooke prepare to spend the summer in Los Angeles together.

Tree Hill residents are surprised to learn that a couple will indeed get married. Brooke tries to adjust to life after the robbery at "Clothes Over Bros". Nathan and Haley receive devastating news and Nanny Carrie's return creates more blanks than answers, after she kidnaps Dan - whose life is in jeopardy.

As the gang returns from Utah, Brooke and Julian are engaged, Haley learns that she is pregnant, Nathan must leave for training camp, and Clay and Quinn are assaulted and shot by Katie.

As the situation at the hospital worsens; Nathan makes a huge decision regarding his career. Brooke and Julian take Jamie for the day, while Victoria and Millicent hatch a plan.

As Brooke and Haley prepare to re-open Karen’s Café, Nathan and Clay hit the road looking for new prospective clients. Meanwhile, Chase leaves for the Air Force leaving behind a disappointed Alex and Chuck, and Mouth and Millicent begin their new morning show together.

The search for Nathan becomes increasingly dangerous, and Dan’s life hangs in the balance. Brooke is surprised when her father returns. And Clay and Quinn reconnect with Logan.