Drug-induced hepatotoxicity is a significant and still unresolved clinical problem. The limitation in current knowledge regarding mechanisms of hepatic toxicity renders most of the preclinical review process failing and most of drug-induced hepatic injury remains unpredictable. Current knowledge on the mechanisms of drug-induced liver cell death is reviewed here. The intervention of both intra- and extracellular factors in determining the appearance of drug-induced cell apoptosis or necrosis is also discussed. Finally, the role of both mitochondria and non parenchymal cells are reviewed with respect to approaches useful to manage drug-induced liver injury.