Hepatotoxicity is a common cause of failure in drug discovery and development and is also frequently the source of adverse drug reactions. Therefore, a better prediction, characterization and understanding of drug-induced hepatotoxicity could result in safer drugs and a more efficient drug discovery and development process. Among the 'omics technologies, toxicogenomics (or the use of gene expression profiling in toxicology) represents an attractive approach to predict toxicity and to gain a mechanistic understanding of toxic changes. In this review, we illustrate, using selected examples, how toxicogenomics can be applied to investigate drug-induced hepatotoxicity in animal models and in vitro systems. In general, this technology can not only improve the discipline of toxicology and risk assessment but also represent an extremely effective, hypothesis-generating alternative to rapidly understand mechanisms of hepatotoxicity.