A large number of cardiology clinical trials have mortality as an endpoint unless adequate surrogate endpoints are available. Although there are nine classes of agents used in the treatment of diabetes mellitus, none have shown a mortality benefit in clinical trials. The United Kingdom Prospective Diabetic Study was the first to suggest that metformin given for diabetes mellitus had a trend toward lowering mortality. The accidental discovery of peroxisome proliferator-activated receptors (PPARs) led to the introduction of the thiazolidinediones (TZD), a PPAR agent with a suggestion of a promise for the future. As the incidence of cardiovascular complications related to diabetes mellitus increases, there is a sense of urgency to produce antidiabetic medications that achieve not only nontoxic glycemic control but also improved cardiovascular outcomes. The goal of this review is to aid the clinician to appropriately assess the benefits and risks of TZD use when prescribing for patients.