The cholesterol-lowering agents, known as statins, have been in use for 15 years and are among the most commonly prescribed drugs. Animal studies and premarketing clinical trials have given signals of hepatotoxicity, primarily minor elevations in serum alanine aminotransferase enzyme (ALT) levels. For that reason, all of the cholesterol-lowering drugs have labeling that requires monitoring of liver enzymes. Postmarketing experience, however, suggests that hepatotoxicity is rare and thus it is timely to revisit the issue. The first of the statins, lovastatin, was approved in 1986 and has acquired 24 million patient-years of clinical experience. Minor elevations in liver enzymes, i.e., ALT 3 × the upper limit of normal (ULN) occur in 2.6% and 5.0% of patients on lovastatin doses of 20 and 80 mg/day, respectively. These elevations are reversible with continuing therapy, are dose related, and are probably related to cholesterol lowering per se. Rare cases of acute liver failure (ALF) have been reported with all of the cholesterol-lowering drugs. With lovastatin, the rate is approximately 1/1.14 million patient-treatment years, which is 9% of the background rate of all causes of ALF and approximately equal to the background rate of idiopathic ALF. Monitoring for hepatotoxicity has not been effective in preventing serious liver disease, largely because of its rarity and the poor predictive value of minor ALT elevations. In fact, it may increase patient risk because of needless discontinuation of cholesterol-lowering therapy for false-positive results in patients who are benefiting from treatment.