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- "I believe we're put on this Earth for a reason, Clark. Our task in life is to find out what that reason is. Sometimes we can't do that alone." - Lionel Luthor, Legacy
After Lex crashed en route to his honeymoon, Lionel held a funeral service for his son after the rescue teams came up empty. Martha, Jonathan, Lex's widow Helen Bryce, Lana Lang, and Clark all attended. Lionel publicly denounced Helen, although he couldn't completely have her disposed, due to the special vial of blood he bought from her and the fact that she was the only one who knew where it came from. When Lex returned, Lionel had to prove he had nothing to do with the plane crash.
When Lex stumbled upon the mysterious deaths of his grandparents and learned that Lionel had his parents killed for the insurance money, Lionel schemed to have Lex—and everyone else—believe that Lex is crazy in order to cover up the murders.
To have Lex committed, he had untraceable drugs placed in Lex's drink that made him hysterical, and "cleaned" up his messes that he made in the Luthor Mansion. Lionel then ordered for Lex to receive electroshock therapy at Belle Reve; afterward, Lex remembered little of the last seven weeks.
Lionel wanting to learn more and more about Clark, demanding more on the reports of Clark from Chloe Sullivan. When Chloe arrived in Lionel's office and had no information on Clark, Lionel canceled her column at the Daily Planet and had her father fired. He also sent a mysterious young man named Adam Knight to Smallville to get close to Lana so she could tell him everything there is about Clark.
Later on, Lionel and Lex argued about the project Lex wanted to be in charge of, which resulted in Lionel hiding the lab. He got Dr. Lia Teng to move the lab, but in the end, she and her lab technicians were killed by an unstable inmate that Lionel was experimenting on (Adam Knight). Lionel was not responsible for their deaths, but knew that the FBI suspected him. So he pinned the murders on Lex, framing his own son. Knowing that the destruction of the lab would end his chances of surviving his liver disease, Lionel contemplated suicide, knowing he only had a matter of months.
Lionel then met with Dr. Virgil Swann to ask about the hieroglyphics on the walls of the Kawatche Caves. Dr. Swann didn't give Lionel the information that he needed, but offered another arrangement. Lionel attempted to force his way into the cave wall, but was stopped by Jonathan Kent; they fought, and Lionel watched as the key flew into the wall. Later, he had his people torture Pete Ross, resulting in Pete's departure from Smallville.
With the help of Chloe, Lionel was arrested, but not before setting in motion a few of things. He gave Clark the key to Lex's secret room, ending the friendship between Lex and Clark; had Chloe and her father's safe house compromised, resulting in it exploding; and had Lex's brandy poisoned. Lionel was incarcerated in a transparent prison cell having his lion's mane of hair being completely shaved off.