The film begins in Mexico, where police officer Javier Rodriguez (Benicio Del Toro) and his partner, Manolo Sanchez (Jacob Vargas), stop a drug transport and arrest the couriers. Their arrest is interrupted by General Salazar (Tomás Milián), a high-ranking Mexican official, who decides to hire Rodriguez. Salazar instructs him to locate and apprehend Francisco Flores (Clifton Collins, Jr.), a notorious hit man for the Tijuana Cartel, headed by the Obregón brothers.

Meanwhile, Robert Wakefield (Douglas), a conservative Ohio judge, is appointed to head the President's Office of National Drug Control, taking on the title drug czar. Wakefield is warned by his predecessor and several influential politicians that the War on Drugs is unwinnable. Unbeknownst to Wakefield, his honors student daughter, Caroline (Erika Christensen) has been using cocaine, and develops a drug addiction after her boyfriend Seth (Topher Grace) introduces her to smoking heroin. Caroline and Seth are arrested when a fellow student overdoses on drugs at a party and they unsuccessfully try to dump him anonymously at a nearby hospital. Robert finds out that his wife Barbara (Amy Irving) has known about their daughter's involvement with drugs for over six months.

A third story is set in San Diego, where an undercover Drug Enforcement Administration (DEA) investigation led by Montel Gordon (Don Cheadle) and Ray Castro (Luis Guzmán) leads to arrest of Eduardo Ruiz (Miguel Ferrer), a high-stakes dealer posing as a fisherman. Ruiz, who is hospitalized as the result of a gunshot wound from the arrest, decides to risk the dangerous road to immunity by giving up his boss: drug lord Carlos Ayala (Steven Bauer), the biggest distributor for the Obregón brothers in the United States. Ayala is indicted by a tough prosecutor, hand-selected by Wakefield in an attempt to send a message to the Mexican drug organizations.
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