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Although drug-induced liver injury is a rare clinical event, it causes significant morbidity and mortality, making it the leading cause of acute liver failure. The predominant clinical presentation is acute hepatitis and/or cholestasis, although almost any clinical pathological pattern of acute or chronic liver disease can occur. The pathogenesis of drug-induced liver disease usually involves the drug or metabolites that directly affect cellular biochemistry or elicit an immune response. Susceptibility to drug-induced hepatotoxicity is also influenced by genetic and environmental risk factors. Unpredictable, low-frequency, and idiosyncratic reactions often occur in the context of high levels of mild asymptomatic liver damage and, although difficult to predict, can be detected by monitoring serum alanine aminotransferase levels. The development of various drug-injury networks has played a key role in expanding our knowledge of liver injury associated with drugs, herbs, and dietary supplements.