As Clark and Lana get more romantically close to each other, the comatose Dr. Fredrick Walden recovers and repeats the sentence "the day is coming, and he will rule the world" many times. He believes that Clark Kent is a menace to mankind. He escapes from the mental institution using a strong power he has achieved and tries to eliminate Clark. Meanwhile, Dr. Helen Bryce returns to Smallville for her engagement party with Lex Luthor, and finds her office broke in and the blood sample of Clark Kent stolen. But who took the blood sample and her office files? Lionel or Lex? Clark is asked by Lex to be the best best man, and Martha and Jonathan Kent to replace his missing parents, as Clark begins hearing voices coming from his spaceship. Also, the evil Lionel Luthor continues playing mind games by trying to poison the relationship of Helen and Lex, as well as Chloe and Clark by offering her an intern job in Metropolis in exchange for her to investigate Clark. But unfortunately, Lionel overhears the revelations of Dr. Walden to Lex about Clark being an alien.

When Jonathan goes to Smallville Medical Centre for a physical examination, his doctor diagnoses arterial blockage and recommends a triple bypass heart surgery procedure. Meanwhile, Vince Davis, the older brother of Clark Kent's friend Garrett Davis, needs a liver transplant - but does not receive one and he dies. His body is sent to Metropolis to be the next test subject of Lionel's experiment by Dr. Lia Teng, who injects his dead body with experimental blood platelets and revives him. When Vince gets sick again (because he needs the life-sustaining blood injections on a daily basis), the unstable Garrett loses control and becomes a threat to the patients, employees, and visitors of the hospital by showing up at the hospital with a kryptonite-infused bomb strapped to himself, threatening to blow himself up unless his brother receives a new liver transplant. Clark must try to find a way to defuse the situation during Jonathan's heart surgery, while the overzealous Sheriff Adams wants to kill Garrett in any way possible... even at the expense of the hostages. Meanwhile, Chloe does some investigating for Lex of Dr. Teng and learns about the mysterious blood platelet serum she's manufacturing and about the first test subject: Adam.

Alicia Baker returns, and with the help of Red Kryptonite, elopes in Las Vegas with Clark. Lana offers a sexual relationship to Jason in an attempt to win him back. Lionel comes back to Lex with a peace offering.