Rhabdomyolysis is a disorder in which injury to muscle results in leakage of myocyte intracellular contents into the plasma. It has been associated with a tremendous number and diversity of clinical conditions and substances. Several physiological and biochemical mechanisms for this syndrome have been described. The most likely etiology of rhabdomyolysis in patients presenting to the emergency department is ingestion of drugs of abuse, most commonly ethanol, heroin, amphetamines, cocaine, and other sedatives or stimulants. In this article, the association between rhabdomyolysis and drugs of abuse is explored, as well as its diagnosis and treatment.