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Walter White, a chemistry teacher with a pregnant wife and a son with cerebral palsy, develops stage three lung cancer. Walter enters the dangerous world of drugs by using his chemistry knowledge to cook crystal meth in order to support his family when he's gone. Jesse, a former student, is his meth-cooking partner. They use an RV to cook the meth out in the desert. Their arrangement runs into trouble when two dealers whom Jesse had tried to sell meth to appear and threaten to kill Walter when one of the drug dealers falsely associates Walter with the DEA. Walter offers to teach them his meth recipe, but he gasses them with phosphine before they can shoot him. Walter drives away in the RV with the two apparently dead men and the injured Jesse.

Walter and Jesse discover that Krazy-8, one of the two meth dealers, is still alive. They decide to kill him and dispose of the other dealer's body, flipping a coin to see who has to kill Krazy-8. They shackle Krazy-8 to a pole in Jesse's basement with a bike lock while they figure out exactly how they're going to dispose of them. Jesse, who had won the coin toss, tries to dissolve the dead dealer's body in hydrofluoric acid on Walt's recommendation, but botches this attempt by dissolving the unlucky dealer in his bathtub against Walt's wishes. The acid melts straight through the bottom of Jesse's tub and a mass of acid, blood, and body matter falls through the ceiling of his first floor.

Meanwhile, Walter cannot decide whether or not he can kill Krazy-8, who knows Walter's name and where Walter works. Walt brings Krazy-8 dinner, but things turn badly when Walter collapses in a coughing fit, letting the plate fall to the ground. When he wakes up, he tells Krazy-8 that he has cancer, and is hiding it from his family. After Walt cleans up the mess and returns with more food, the two end up talking about their lives while eating and drinking in the basement. After learning about Krazy-8's life, Walter decides to free him. As he grabs the key from the kitchen, he realizes that Krazy-8 kept a shard of the dinner plate and planned on stabbing Walt with it upon being freed. Walt pretends to free Krazy-8, but instead strangles him with the bike lock that they had placed around Krazy-8's neck.

Hank, Walter's brother-in-law drug enforcement agent, is trying to find the new kingpin of crystal meth (unaware that it is Walter). Walter's wife, Skyler, begins to cry when Walter confesses to everybody that he has cancer, while Jesse goes to visit his parents, only to figure out that his brother is smoking pot. Jesse accepts the blame for the pot and is kicked out of the house. When his brother asks for the weed back, Jesse throws it on the ground and crushes it.

Walter, now willing to go through with the radiation therapy, is determined to pay for it himself using money made from cooking meth. Jesse, who has been cleaning up his act, sells the meth they'd made before and brings Walt the money. They then come to an agreement: Walter cooks the meth while Jesse sells it. Jesse discovers that Walter has lung cancer and figures out that he's cooking meth to help his family when he's gone.

Walt has Jesse try and sell in bulk to Tuco, a violent psychopath who has taken over Krazy-8's distribution. Tuco refuses to pay anything for what Jesse has brought, and proceeds to brutally beat him when he attempts to flee. Walt confronts Tuco, who attempts to take advantage of them again, but Walt earns his respect by blowing up the top floor of his hideout. Tuco agrees to go into business with them.

In the season finale, Walter and Jesse cut over the counter medicine out of their recipe, planning and executing a heist for a more potent chemical replacement. They begin steady business with Tuco.

Although AMC doesn't know a solid plot for the second season, it will go deeper inside Walter's life, Skyler's baby girl, and finding the kingpin.