Drug-induced hepatotoxicity is a frequent cause of liver injury. 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 participation of the parent drug or metabolites that either directly affect the cell biochemistry or elicit an immune response. Each hepatotoxin is associated with a characteristic signature regarding the pattern of injury and latency. However, some drugs may exhibit >1 signature. Susceptibility to drug-induced hepatotoxicity is also influenced by genetic and environmental risk factors. Unpredictable, low-frequency, idiosyncratic reactions often occur on a background of a higher rate of mild asymptomatic liver injury and, although difficult to predict, they may be detected by monitoring serum alanine aminotransferase levels. Recent and future advances in toxicogenomics and proteomics should improve the identification of risk factors and the understanding of idiosyncratic hepatotoxicity.