Fibrates, widely used to treat lipid disorders, are weak and relatively nonspecific agonists of the peroxisome proliferator–activated receptor α (PPAR-α). A number of potent and selective PPAR-α agonists have been developed, but little is known about their safety and efficacy. Nissen and colleagues report the safety and efficacy of a PPAR-α agonist, LY518674, assessed in 2 separate randomized clinical trials: one involving patients with atherogenic dyslipidemia and the other, patients with hypercholesterolemia. In both trials, the authors found that LY518674 decreased triglyceride levels and increased high-density lipoprotein cholesterol levels relative to placebo. In the dyslipidemia trial, patients receiving LY518674 experienced an increase in low-density lipoprotein cholesterol (LDL-C) levels. In the hypercholesterolemia trial, LY518674 as monotherapy reduced LDL-C levels, but there was no further reduction in LDL-C levels when LY518674 was added to atorvastatin. Overall, patient outcomes with LY518674 were similar to those with fenofibrate, and both LY518674 and fenofibrate were associated with potential oncogenesis, renal dysfunction, rhabdomyolysis, and cardiovascular toxicity.