During the preclinical, early clinical, late-stage clinical, and postmarketing phases of the pharmaceutical discovery and development process, one important aspect of drug safety assessment involves monitoring for possible drug-induced hepatic injury. Hepatic injuries vary in nature from direct, intrinsic effects that are observed in most recipients and more than one species to rare idiosyncratic responses seen only in a few clinical subjects. Histological types of injuries vary from hepatocellular to hepatobiliary with multiple cellular effects characteristic of each type. Of the various clinical laboratory markers for hepatic injury, serum transaminases, especially alanine aminotransferase (ALT), are the most universally important indicators for studies ranging from early preclinical animal testing to postmarketing patient monitoring. This review examines the characteristics of hepatic toxicity that result in serum ALT changes, the differences in the etiology of hepatic responses which govern when liver injury is most likely to be detected during the four phases of the drug discovery and development process, and those modulating factors which affect the utility of ALT as a dependable marker of hepatic injury in clinical populations. The paper concludes with a summary of some ancillary methods for early preclinical screening such as in vitro metabolism and toxicity assays, gene and protein expression analysis, and some strategies for enhancing the probability for the early detection of idiosyncratic hepatotoxic responses which are infrequent but significant factors in the safety assessment process.