Drug-induced liver injury depends initially on development of hepatocyte stress and cell death, which can be induced directly by parent drugs or by toxic metabolites. Hepatocyte stress can lead to activation of built-in death programs for apoptosis or necrosis. Subsequently, the innate immune system's participation is recruited. The interplay between proinflammatory and anti-inflammatory components of innate immune system determines the outcome of drug-induced liver injury. Both environmental factors and genetic differences in cellular responses to stress and the innate immune response may account for different susceptibilities between individuals to drug-induced liver injury.