A high rate of myocardial metabolism is needed to generate energy to sustain cardiac contractile activity. Typically, energy generation occurs through the metabolism of free fatty acids (FFAs), glucose, and lactate. However, in individuals who are insulin resistant or who have diabetes mellitus, excessive FFA metabolism occurs in the heart. Pharmacologic manipulation of myocardial metabolism may be beneficial in these patients. There is evidence that the thiazolidinediones (TZDs), aside from exerting insulin-sensitizing effects on fat and skeletal muscles, also act on the myocardium as a result of reducing circulating fatty acid concentrations. Animal studies have shown that the TZDs influence the expression and function of glucose transporters in the heart, leading to improved glucose metabolism. Recent experiments have also shown that administration of TZDs may protect against myocardial injury associated with ischemia and may improve recovery of function during the postischemic period. This article provides a review of the potential beneficial effects of the TZDs on myocardial metabolism.