Javier Rodriguez (BENICIO DEL TORO) and his partner Manolo Sanchez (JACOB VARGAS) are Tijuana State cops who find themselves tempted and/or coerced within a police department where drugs, drug trafficking and related money have corrupted others. They eventually find themselves somewhat reluctantly working for General Arturo Salazar (TOMAS MILIAN), Mexico's apparent number one drug fighter who wants them to shut down the Tijuana drug cartel, first by capturing assassin Francisco Flores (CLIFTON COLLINS JR.).
Robert Wakefield (MICHAEL DOUGLAS) is a conservative Ohio State Supreme Court Judge who's just been appointed by the President as the nation's new drug czar. While he has his hands full collecting information about the post, the state of the war on drugs and establishing collaborative efforts with Mexico to stem the drug trade, he and his wife, Barbara (AMY IRVING), must contend with their 16-year-old daughter, Caroline (ERIKA CHRISTENSEN). Although she's smart and a scholastic overachiever, she's also a drug addict and enjoys getting high with her friends including Bowman (COREY SPEARS), Vanessa (MAJANDRA DELFINO) and boyfriend Seth Abrahms (TOPHER GRACE).
Montel Gordon (DON CHEADLE) and Ray Castro (LUIZ GUZMAN) are undercover DEA agents hoping to crack an infamous drug cartel led by Juan Obregon (BENJAMIN BRATT). Their busting of middle-rung drug trafficker, Eduardo Ruiz (MIGUEL FERRER), leads to the arrest of Carlos Ayala (STEVEN BAUER) who turns out to be a drug baron and not the upstanding business and family man he appears to be.
That all comes as a shock to his pregnant wife, Helena (CATHERINE ZETA-JONES), who consults with attorney Arnie Metzger (DENNIS QUAID) while trying to figure out how to deal with such unexpected revelations as well as threats from the cartel and being trailed by the DEA. As the presence of drugs and the war on them rages on, those various people attempt to confront the related issues that directly affect them.