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Substance-related disorders are common and cause significant medical, social, and psychological problems among users and those around them. This DSM category comprises a protean set of clinical syndromes, with the different substances exerting various effects. The authors review the diagnosis, natural history, biopsychosocial underpinnings, testing, and treatment of these disorders, focusing on the latest and most practical findings from the research and clinical literature. The future directions of the understanding and treatment of substance-related disorders are discussed.