OBJECTIVE To describe the most important potential adverse effects related to statin therapy, discuss mechanisms of toxicity and drug interactions, and suggest approaches for enhancing safety with statin therapy. METHODS Large-scale clinical trials, government databases and papers, and recent studies of statin safety. METHODS By the author. METHODS By the author. RESULTS The number of patients requiring intensive therapy with statins to achieve lipid goals is climbing, and as the number grows, so does the potential for adverse effects with these agents. The most detrimental adverse effects of statins are hepatotoxicity and myopathy. Liver dysfunction induced by statins is rare and usually mild, with asymptomatic transaminase elevation or acute cholecystitis. Progression to liver failure is exceedingly rare, and transaminase elevations is usually reversible with dose reduction. Statin-associated myopathy is generally a concern when patients have more than one risk factor for muscle syndromes, such as an elderly patient with poor renal function. Drug interactions represent an additional concern, especially for atorvastatin, lovastatin, and simvastatin, all of which are metabolized by the important 3A4 isoenzyme of the cytochrome P450 system of the liver. CONCLUSIONS The benefits of all available statins for the treatment or prevention of cardiovascular disease outweigh any potential risks of therapy. For patient groups most susceptible to adverse effects, such as the elderly and those on multiple medications, clinicians should consider the use of statins that are least likely to interact with other medications.