Shortly after the end of the Y2K crisis, Superman began noticing Lois Lane was acting strangely. She seemed paranoid and suspicious, even of his close friends. She stayed out late nights without explaining where she was going. When Superman confronted her, she told him she was leaving. Then she attacked him.

When that happened, Superman immediately realized what had been going on. It wasn't Lois at all; it was really the Parasite, who had, after his encounter with Strange Visitor, gained the ability to shape shift and to drain peoples' memories and personalities. For several weeks Parasite had been impersonating Lois, keeping her hidden away somewhere outside Metropolis.

Superman searched high and low for his wife. He broke into Lexcorp Towers, sure that Luthor would have some information. He even enlisted the help of Batman, who finally tracked Lois down to a cave some miles outside of Metropolis.

No sooner was Lois returned to him, however, than the Man of Steel found himself in very serious trouble. He had been, amazingly, feeling more and more under the weather for weeks, and his body had begun to give off a strange greenish glow. Finally he collapsed, and was rushed to STAR Labs.

The doctors at STAR, led by Kitty Faulkner and aided by Ray Palmer (also known as the Atom), soon discovered that Superman was being poisoned internally by a small fragment of kryptonite. This small fragment had somehow been introduced into his body, and had developed into a tumor which was killing the Man of Steel by inches. The Atom suggested the solution: using his patented shrinking technology, he would miniaturize Superboy, Supergirl, and Steel and send them into Superman's body to destroy the tumor.

While Superman's friends prepared for their journey, Lois Lane was tracked down by La Encantadora, who confessed that she had been paid to poison Superman. Unfortunately, the same person who had paid her got wind of her confession and sent Deathstroke the assassin to kill her.

While Lois and the Atom tried to save Encantadora from Deathstroke, inside Superman's body Superboy fought the kryptonite tumor, smashing it to pieces. Once the tumor was destroyed, Superboy, Supergirl, and Steel made their way out of Superman's body. The Man of Steel regained consciousness and saved Encantadora just as Deathstroke was preparing to land a killing blow.

Although Superman's life had been saved, things were about to get decidedly strange for the Man of Steel...