Fibrates are an important class of drugs for the management of dyslipidemia. This class of drugs is generally well tolerated but is infrequently associated with several safety issues. Fibrates, most likely by an effect mediated by peroxisome proliferator-activated receptor–α, may reversibly increase creatinine and homocysteine but are not associated with an increased risk for renal failure in clinical trials. Fibrates are associated with a slightly increased risk (<1.0%) for myopathy, cholelithiasis, and venous thrombosis. In clinical trials, patients without elevated triglycerides and/or low high-density lipoprotein cholesterol (HDL) levels, fibrates are associated with an increase in noncardiovascular mortality. In combination with statins, gemfibrozil generally should be avoided. The preferred option is fenofibrate, which is not associated with an inhibition of statin metabolism. Clinicians are advised to measure serum creatinine before fibrate use and adjust the dose accordingly for renal impairment. Routine monitoring of creatinine is not required, but if a patient has a clinically important increase in creatinine, and other potential causes of creatinine increase have been excluded, consideration should be given to discontinuing fibrate therapy or reducing the dose.