Drug-induced liver injury (DILI) remains a leading reason why new compounds are 
dropped from further study or are the subject of product warnings and regulatory 
actions. Hy's Law of drug-induced hepatocellular jaundice causing a 
case-fatality rate or need for transplant of 10% or higher has been validated in 
several large national registries, including the ongoing, prospective U.S. 
Drug-Induced Liver Injury Network. It serves as the basis for stopping rules in 
clinical trials and in clinical practice. Because DILI can mimic all known 
causes of acute and chronic liver disease, establishing causality can be 
difficult. Histopathologic findings are often nonspecific and rarely, if ever, 
considered pathognomonic. A daily drug dose >50-100 mg is more likely to be 
hepatotoxic than does <10 mg, especially if the compound is highly lipophilic or 
undergoes extensive hepatic metabolism. The quest for a predictive biomarker to 
replace alanine aminotransferase is ongoing. Markers of necrosis and apoptosis 
such as microRNA-122 and keratin 18 may prove useful in identifying patients at 
risk for severe injury when they initially present with a suspected 
acetaminophen overdose. Although a number of drugs causing idiosyncratic DILI 
have HLA associations that may allow for pre-prescription testing to prevent 
hepatotoxicity, the cost and relatively low frequency of injury among affected 
patients limit the current usefulness of such genome-wide association studies. 
Alanine aminotransferase monitoring is often recommended but has rarely been 
shown to be an effective method to prevent serious DILI. Guidelines on the 
diagnosis and management of DILI have recently been published, although specific 
therapies remain limited. The LiverTox Web site has been introduced as an 
interactive online virtual textbook that makes the latest information on more 
than 650 agents available to clinicians, regulators, and drug developers alike.