Chloe finds herself hooked in foreign exchange student Mikail Mxyzptlk's underground gambling ring at school, but he wields an influencing power over the football team which causes it to lose its game and causes Chloe to lose a bet.
Clark returns to Smallville as Kal-El, ready to claim his destiny and begins to track down a kryptonite crystal to help him do it. Martha tries to figure out how to help Clark before it's too late, turning to a colleague of Dr Swann's.
Clark and Lois begin to probe into the death of Chloe, only to be stopped by a military general who turns out to be Lois' father, General Sam Lane. Lois suspects her dad knows a little more than he'll admit about Chloe's murder, and Clark learns that he has been in contact with Lex very recently.
Clark must contend with a girl whose attempts to gain popularity through plastic surgery have gone tragically wrong, as the surgery, done with the aid of kryptonite, causes her to destroy people with the touch of a kiss. She's also decided her next kissing victim will be Lana. Lana, meanwhile, tries to maintain the secrecy of her relationship with Jason to keep Clark in the dark.
After joining the school football team, Clark is immediately promoted by new coach Jason to quarterback status after Jason experiences a surprising wrath from the former quarterback. When Clark tries to determine why the quarterback went haywire, he learns that the cheerleaders are attempting to turn the boys into mindless drones by infusing the water with kryptonite.
Jonathan's wallet is stolen by a thief who saves him from being hit by a car, but Clark's attempt to catch the thief proves fruitless when the thief is inexplicably faster than him.
A shrill ringing in Clark's ears leads him to visit the prison which houses Lionel Luthor, but when Clark sees Lionel trying to attack Lex with a glowing stone, his attempt to stop the incident causes himself and Lionel to somehow swap bodies. The newly transformed Lionel begins causing destruction across Smallville, while Clark, stuck in prison within Lionel's body, is forced to devise a solution that will stop Lionel from misusing his powers.
Lana recites a passage from a spell book she's picked up which dates back to the 1600s, but the effect of the spoken words is that she, Chloe, and Lois all become possessed by the spirits of three burned witches.
Lex is accused of killing a woman he bedded, but Clark thinks he's innocent and asks Lionel for help. Lionel, professing to have turned a corner, agrees to help him clear his son's name, but there is a price for Clark to pay. Meanwhile, Lana meets Jason's parents, but soon begins to suspect that his mother may have actually been present during their time in Paris.
An experiment at Luthercorp brings the release of a dangerous toxin into the Smallville air, which causes people's greatest fears to come to consciousness. As a result, after their fears overwhelm their senses, Clark, Chloe, Lana, and Jason slip into a coma. Lex, in an attempt to cure everyone, takes an untested drug that might do the trick. Meanwhile, a mysterious and generous source helps get Lionel's conviction repealed.
Alicia returns to Smallville following her release from the hospital, and with her claims of being cured, Clark seems willing to give their relationship another shot. When her old intensity begins to push him away, however, she uses red kryptonite on him which brings out the bad in him and leads him to take her to Las Vegas to get married. Meanwhile, Lana contemplates using sex to bring Jason back to her.
Clark's new girlfriend, Alicia, is accused of savagely attacking Lana and Jason, but after taking her defense when she proclaims her innocence, Clark has a different conclusion when the evidence begins to mount against her. Alicia then gets retribution against Clark by orchestrating a situation in which Chloe becomes a witness to his powers. Meanwhile, Jason's mother comes to Smallville to try and strike a deal with Lex.
Clark is recruited to play football at Met U, and the school sends Geoff, its star player, to try and entice Clark with a peek at the school's benefits.
Lois accidentally hits a dog while driving, but when she takes it to the Kent farm to help it recuperate, it soon becomes clear that this dog has some superpowers. Clark and Lois learn that the dog was a discarded experiment at LutherCorp and recently used to assist criminals. When some thieves kidnap Lois and Clark is affected by Kryptonite, the dog is the one who must rescue them both.
Clark and Lana follow Jason and Lex to China in hopes of beating them to the discovery of an elusive Kryptonian crystal. Lex, however, has information about the crystal, but decides to keep silent. In China, after Clark finds an artifact which takes him in the direction of the crystal, he quickly finds that he must fight the witch Isobel who has once more possessed Lana and plans to steal the crystal.
Lois' little sister Lucy comes to Smallville, prompting old bitter feelings from Lois when Lucy begins to dazzle everyone in town with her immense charm, but when Clark finds Lucy pilfering cash from a bar, he confronts her and realizes there is a much less rosy side to her than the one everyone sees.
A kryptonite explosion causes Lex to split into two, unleashing his evil twin Alexander upon Smallville, who immediately barricades Lex in his mansion and goes off to kill Clark and Chloe. Soon after, Alexander attempts to lead Lionel back down his old, dark path and bully Lana into living with him.
Chloe is surprised to learn that she has been nominated as prom queen at school and asks Clark and Lana to accompany her to the dance. Soon after Chloe's main competition for the crown, Dawn, crashes her car into a kryptonite-filled chasm, Dawn's newly-released spirit inhabits her body along with Clark and Lana's, making them do some unexpected and, in Chloe's case, terrible things.
Clark comes on with a case of amnesia courtesy of a boy with the power to make people forget things, however Chloe must quickly try and remind Clark of the superpowers he possesses and keep him from accidentally revealing them to others. When Clark meets Lana all over again, he falls for her and decides to tell her about his powers, but Lex deviously tries to manipulate Clark's condition and get him to reveal where the three stones are located.
Clark and Lana find a seemingly abandoned infant in the cornfield and immediately bring it to the Kent farm. When the baby ages seven years in just a few days, they realize some factor is making the baby age at a dangerously fast speed and try to figure out stop the process. Meanwhile, Genevieve demands that Lionel murder Lana or face more prison time.
When the school photographer creates a carbon copy of high school for which he intends to kidnap students and recreate its glory forever, Chloe is his first hostage, leading Clark to try and stop his demented plan. The Teagues, meanwhile, kidnap Lex and Lionel in order to get at the location of the crystal, but Genevieve discovers that it's in Lana's possession and decides to finally obtain it.
Clark heads to the cave to seek advice from Jor-El after a terrible nightmare convinces him that Smallville is about to face a serious threat. He is told to reunite the three crystals or Earth will succumb to a fate that is too great for even his powers to halt.