Cocaine abuse kills thousands every year. Preexisting coronary artery disease appears to account for many of the deaths, but often the mechanism is much more complex. There exists a widely held but utterly mistaken notion that cocaine-related deaths are due to drug overdose. Except in the case of drug couriers ("body packers") with massive drug exposure, death is not dose related, and cocaine blood levels cannot be used to predict toxicity. Most deaths occur after prolonged drug use, which initiates a series of changes at the molecular, cellular, and tissue levels. All of these changes favor sudden death. Potentially lethal myocardial alterations include hypertrophy, fibrosis, and microangiopathy. Recently it has become clear that genetic causes, such as fully or partially expressed congenital long QT syndrome, may also play a role. The relative importance of each of these factors is reviewed.