Given the fact that as many as 9% of all adverse drug reactions involve toxic effects on the liver and with upwards of 50% of all cases of fulminant hepatic failure being ascribed to acetaminophen and other agents, the safe use of medications takes on an even greater importance whenever the prescription of potentially hepatotoxic drugs to patients with underlying liver disease is considered. In general, it is thought that most drugs can be safely administered in the setting of liver disease without an increased risk of hepatotoxicity, although the evidence on which this statement is based often relies more on clinical judgement than on clinical studies. Several drugs appear to have an increased risk of hepatotoxicity in patients with underlying liver disease based on either clinical reports or extrapolated pharmacological data. These agents, including methotrexate, niacin and the antiretroviral and antituberculosis drugs, carry warnings about their use in patients with a variety of liver conditions. The data supporting the hepatotoxic risk of scores of additional drugs, such as the 3-Hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase inhibitors ("statins"), the newer thiazolidinediones (rosiglitazone, pioglitazone), and tamoxifen, among others, in patients with liver disease are generally lacking by evidence-based studies. However, clinical and biochemical monitoring is routinely recommended or required, often to make up for the lack of information on the true risk of clinically significant liver toxicity of these agents in individuals both with and without underlying liver disease. This article will review what is and what is not known about prescribing in the setting of acute and chronic liver disease and offers recommendations to help promote the safe and rational use of potentially hepatotoxic medications in these patients.