Peroxisome proliferator-activated receptors (PPARs) are central regulators of lipoprotein metabolism and glucose homeostasis that are considered particularly useful for improving glycemic control and comorbidities in patients with type 2 diabetes mellitus. Clinical trials of PPAR-alpha agonists have demonstrated efficacy in reducing cardiovascular events; however, these benefits have been confined to subgroups of patients with low levels of high-density lipoprotein cholesterol or high levels of triglycerides. While activators of PPAR-gamma reduce early atherosclerotic lesions and reduce cardiovascular events, these agents have the effect of increasing fluid retention in patients, which results in more hospitalizations for congestive heart failure. Future studies of PPAR-gamma agonists or dual PPAR-alpha/gamma agonists will require further delineation of the risk profile to avoid adverse outcomes in susceptible patients.