While working as a volunteer with Pete at Smallville Youth Center, Clark receives a distress phone call from Lana, who is shot by Adam. His further investigation shows that the call was made from the future because of a time/space porthole created by a massive electrical surge from a downed power line fitted with meteor rocks, during a coming thunderstorm. Clark must try to save Lana and change the future. Meanwhile, Lionel Luthor shuts down the obscure Merton Laboratory and the research that Dr. Lia Teng is developing with blood platelet, which were finally revealed to have been developed from the vial of Clark Kent's blood. Adam becomes aware that he has less than 12 hours to be injected with the serum, otherwise he will die. He escapes, kills Dr. Teng and her whole team, and Lex is framed as responsible for the mass murder. Adam then sets out to find Lana to know if she still has an extra vial of serum for him. Lex later meets with an FBI agent, named Frank Loder, who enlists his help to bring down Lionel Luther, who also confides in an associate of his about his research and reveals the reason for it: Lionel himself is dying from a rare liver disease.

While on the roof of the barn, Jonathan is contacted though the octagonal key and Clark saves him from a fall. Clark goes to the Kawatche caves with the key trying to find an explanation for what happened, when Lionel Luthor unexpectedly appears and expresses his suspicion towards Clark. Lionel goes to New York and secretly meets with Dr. Virgil Swann and proposes an association to investigate Clark. Meanwhile, the FBI is revealed to have bugs in Lex's mansion for a surveillance to obtain evidence against Lionel, and Clark becomes a suspect due to the interest of Lionel in the apparently simple "farm boy". Later, agents, led by Frank Loder, arrive at the Kent farm to search it for the missing octagonal key, leading Clark to mistakenly believe that Dr. Swann betrayed him to Lionel. Meanwhile, Lana cannot seem to make up her mind whether she wants to stay with Clark or not.

Clark Kent decides to disclose his secret to Lana to avoid her from traveling to Paris, and he invites her for dinner at the Kent farm. But things take a turn when the dangerous teenager Emily Eve Dinsmore, the six-year-old girl (from the episode 'Accelerate') had matured into a grown-up and still obsessed with Lana, escapes from the institute where she is interned. She kills the new owner of Talon and kidnaps Lana. Meanwhile, Chloe joins forces Lex trying to find evidence to send the powerful Lionel to prison for the murder of Lex's grandparents. Elsewhere, Pete is threatened by the corrupt FBI agent, Frank Loder, who is still trying to find what he knows about Clark. Clark then decides against telling Lana his secret after Pete reveals to Clark about the pain of the ability to keep his secret and Pete decides to move away from Smallville to live with his now-divorced mother in Wichita.

At the Kent farm, Clark Kent is surprised in the middle of the night by a naked young woman claiming that she is Kara from Krypton, and asking him to go with her somewhere through the Kawatche caves to be "re-born" with the spirit of Jor-El. Kara also forces Jonathan to reveal the secret deal he made with Jor-El at the beginning of the season. Meanwhile, Clark decides to testify against Lionel to keep him in prison. Lionel sends a key of the secret chamber in the Luthor Mansion to Clark where he finally discovers the reason for the last three years of Lex's personal investigation of him, and he ends his friendship with Lex. Agent Loder continues investigating Clark's origins, until Kara finds him eavesdropping on the Kents and she eliminates Loder for good. Also, Lana leaves for Paris and Chloe and her father are included in the witness protection program. Events come full circle as Jonathan unsuccessfully tries to stop Clark from traveling through a dimensional gateway in the cave wall, Martha observes a Kryoptonia symbol that appears in a open field, Lex is alone in the mansion when he had a drink of brandy which is poisoned, Chloe and her father arrive at a FBI safe house... which explodes with them still inside, and Lionel accepts his new look in prison, but satisfied knowing that his revenge against all those involved with his incarceration has been accomplished.