The film opens with Nick Naylor (Aaron Eckhart) appearing on Joan Lunden's daytime talk show, along a doctor, a senator's aide, and a teenage boy with cancer. As he's introduced, the audience spits at him. The screen freezes, spittle in midair, while Naylor explains what he does for a living in a voice over. He works for the Academy of Tobacco Studies, and he represents Big Tobacco. The Academy is supposed to research links between disease and smoking, and has never been able to find anything conclusive.
On the show and throughout the film, he takes the offensive position (in both senses). On Joan Lunden's show, he protests that in no way would he want a potential customer to die, and accuses the doctor of profiting off cancer patients.
His immediate nemesis is Senator Ortolan Finisterre (William H. Macy), a Birkenstock-wearing Vermonter whose office is decorated with cheese and bottles of maple syrup. Senator Finisterre wants to plaster a graphic skull-and-crossbones picture on every pack of cigarettes.
Through all of this, Naylor is also trying to maintain a relationship with his son Joey (Cameron Bright). Naylor's boss BR (J.K. Simmons) wants ideas on how to make smoking sell. "We don't sell Tic Tacs, we sell cigarettes. And they're cool, available, and addictive. The job is almost done for us." Naylor has the idea of product placement in movies.
He takes Joey on the trip to Los Angeles to meet with an agent about putting more smoking in movies. Naylor is divorced, and shares custody of his son. His son is rather uncomfortable with his father's profession, but Naylor is as great arguing with his son as he is with the press and starts to win him over. Naylor portrays himself as being on the side of freedom and personal choice.
On a side trip, Naylor takes a briefcase full of cash to the original Marlboro Man Lorne Lutch (Sam Elliott) who is dying of cancer. There's no strings attached; Lutch can just keep the money. A suspicious Lutch asks why he can't just go to the press. Naylor suggests he do exactly that, and recommends which reporter to talk to. Lutch can go on TV, denounce the tobacco industry, and donate the money to a worthy cause. Donate? Well, if he denounces them he can't keep any of the blood money. Naylor leaves, confident that Lutch will keep quiet.
Back in DC, he debates Senator Finisterre on Dennis Miller's show. A caller threatens Naylor with death for being responsible for millions of deaths. Naylor brushes the threat off, but he's kidnapped. The kidnapper (Jeff Witzke) covers Naylor in nicotine patches and leaves him naked in the lap of the Lincoln Memorial. Ironically, his smoking gave him a resistance to the nicotine, otherwise he would have died.
Naylor is interviewed by a reporter for a Washington paper, but ends up seducing her. He's confident of some positive press, but is shocked when she gives away all of his secrets. She was having sex with him to get the story. She tells about the hush money to Lutch, the movie deal, and his weekly meeting with the MOD Squad: the Merchants of Death, gun and liquor lobbyists (there's a funny bit where he one-ups them on how many people his industry kills).
The Academy distances itself from Naylor, who is shattered for a while. Some supportive words from his son inspire him to fight back. He reveals that the reporter was having sex with him to ruin her career, and agrees to appear in front of Senator Finisterre's committee. He comes out swinging again, accusing Vermont's cheese of clogging arteries and causing heart disease. When asked if he would let his own son smoke, he points out that his son is under 18 and that would be illegal. Pressed for what he would do on his son's 18th birthday, he says that if his son wants a cigarette, he'll buy him one.
Outside the hearing, BR offers him his job back but Naylor turns him down. Good timing: shortly thereafter, the tobacco industry settles for billions and the Academy is shut down. Joey wins the school's debating contest, and Naylor finds new clients: "Look into the mirror and repeat: 'There is no conclusive scientific evidence linking cell phone usage and brain cancer.'"
Apart from the plot, the film is filled with absurd little cutaways. Naylor has a weird fantasy where's he's starring in a hotel safety video. The gun lobbyist has some trouble with the Senate metal detector. Naylor imagines other industries that can use help, like seal clubbers.