While foes such as General Zod, Mongul and Doomsday can physically challenge Superman on their own, many of the Man of Steel's foes weaken him via Kryptonite. These include Metallo, Conduit, and Kryptonite Man, some of whom have incredible physical strength. Superman's most well-known foe, Lex Luthor, is still known for using the irradiated metal for his own purposes.
This weakening agent has been used to literally bring the Last Son of Krypton to his knees, with Luthor typically being the foe smiling in victory whenever it happens. This reliance on kryptonite once proved incredibly deadly for Lex Luthor himself, prompting a continually convoluted storyline that resulted in a deal with the devil. Here's how Luthor's quest for immortality nearly killed him twice.
Ever since he saw the effect that Metallo's kryptonite had on Superman, Lex Luthor was determined to use it to taunt and kill the Man of Steel himself. He would take Metallo's kryptonite "heart" and fashion himself a ring with which to keep Superman at bay. His tests had determined that the element, while radioactive toward Kryptonians, was harmless toward humans. This information, unfortunately for Luthor, turned out to be false. Consistent exposure to kryptonite is particularly carcinogenic toward humans, essentially having a slower version of its effect on Kryptonians. This results in Lex developing cancer, and he amputates his hand in an attempt to stave off.
Unfortunately for him, this was too little, too late, with the cancer having spread to the rest of his body already. Lex hatches a plan to extend his ironically shortened life by way of a new body. Faking his death in a plane crash, Luthor has his brain given a new cloned body in Roger Stern and Bob McLeod's Action Comics #670. Seemingly less genetically prone to the obesity and baldness that Luthor's redesign from John Byrne had, this taller, thinner, and much hairier Lex presented himself to the world as his own son. Returning to Lexcorp in his improved clone body, Lex had seemingly turned a new leaf, albeit a still deceitful one.
This cloned Lex still had a disdain for Superman, but he ironically became Supergirl's passionate lover. His alliance with her saw him defending Metropolis more than ever, though he tried to keep his girlfriend out of the fight when Doomsday rampaged through the city. Lex's body would soon begin to deteriorate, however, with the additional advanced aging being a symptom of a mysterious plague that would affect other clones such as Superboy. It was also revealed to the public, thanks to Lois Lane, that Lex Luthor, Jr. was actually a clone of the criminal original. Angry and desperate, Luthor resolved that no one else would have Metropolis if he was denied it.
Accordingly, Luthor threatens to unleash several missiles to destroy the city if Superman attempts to capture him in "The Fall of Metropolis," by Roger Stern, Karl Kesel, Brent Anderson, Louise Simonson, Jackson Guice, Peter Krause and Jon Bagdanove. Luthor at this point is withered away and nearly vegetative, with his weakness compared to Superman more literal than ever.
Luthor would return, better than ever, during the events of Underworld Unleashed. Though he doesn't believe in the existence of souls, Luthor trades his to Neron in exchange for a restored body. Though still bald, this robust and physically fit form returned Luthor to his classic, slim look. Though he eventually regains his soul when Neron is defeated, he still has to face his publicly criminal past. Luthor somehow contrives enough evidence to convince the courts that his past criminal actions were committed by a rogue clone created by the now-defunct Cadmus, all while he had been kidnapped by the company.
This ridiculous ruse was enough to clear Lex's name, and he would go on to reacquire his former kryptonite ring, as well. From there, his pursuits included forming the Injustice Gang to rival the Justice League, and eventually, become President of the United States of America. Though he may have almost died twice, once due to kryptonite of all things, his return proved once and for all that he was truly Superman's greatest weakness.