Drug-induced liver injury (DILI) refers to liver damage caused by over-the-counter and prescription drugs as well as herbal and dietary supplements. Hepatocytes, the main factory cells of the liver, are the primary targets of drug-related injury. During hepatocyte injury, loss of cell integrity results in a leak of liver contents, including a variety of enzymes, into the circulation. Currently, more than 1,000 drugs and herbal products have recognized hepatotoxic properties, with acetaminophen (APAP) being the most common cause of acute liver failure in the United States and amoxicillin-clavulanate the most common cause of severe liver injury worldwide. This review of DILI addresses the epidemiology, classification, pathophysiology, clinical manifestations, diagnosis, common idiosyncratic drug reactions, unusual drug reactions, treatment, and prognosis, with special sections on APAP hepatotoxicity and the approval of prescription drugs by the Food and Drug Administration. Figures show histologic features of DILI, mechanisms of liver injury, genome-wide association study results for lumiracoxib, APAP metabolism, and the Rumack-Matthew nomogram. Tables list classification of DILI, features of idiosyncratic drug reactions, histologic patterns of DILI, haplotypes associated with specific drug-related disorders, and the Roussel-Uclaf causality assessment method. This review contains 5 highly rendered figures, 5 tables, and 54 references.