Drug overdose and poisoning are leading causes of emergency department visits and hospital admissions in the United States, accounting for more than 500,000 emergency department visits and 11,000 deaths each year. This chapter discusses the approach to the patient with poisoning or drug overdose, beginning with the initial stabilization period in which the physician proceeds through the ABCDs (airway, breathing, circulation, dextrose, decontamination) of stabilization. The management of some of the more common complications of poisoning and drug overdose are summarized and include coma, hypotension and cardiac dysrhythmias, hypertension, seizures, hyperthermia, hypothermia, and rhabdomyolysis. The physician should also perform a careful diagnostic evaluation that includes a directed history, physical examination, and the appropriate laboratory tests. The next step is to prevent further absorption of the drug or poison by decontaminating the skin or gastrointestinal tract and, possibly, by administering antidotes and performing other measures that enhance elimination of the drug from the body. The diagnosis and treatment of overdoses of a number of specific drugs and poisons that a physician may encounter, as well as food poisoning and smoke inhalation, are discussed. Tables present the ABCDs of initial stabilization of the poisoned patient; mechanisms of drug-induced hypotension; causes of cardiac disturbances; drug-induced seizures; drug-induced hyperthermia; autonomic syndromes induced by drugs or poison; the use of the clinical laboratory in the initial diagnosis of poisoning; methods of gastrointestinal decontamination; methods of and indications for enhanced drug removal; toxicity of common beta blockers; common stimulant drugs; corrosive agents; dosing of digoxin-specific antibodies; poisoning with ethylene glycol or methanol; manifestations of excessive acetylcholine activity; common tricyclic and other antidepressants; seafood poisonings; drugs or classes that require activated charcoal treatment; and special circumstances for use of activated charcoal. This review contains 3 figures, 22 tables, and 198 references.