An increasing number of clinical and experimental studies have shown that optimizing energy metabolism in the heart is an effective approach to decreasing the symptoms associated with myocardial ischemia. In particular, increasing myocardial glucose metabolism can benefit heart function and/or lessen tissue injury. However, high levels of circulating fatty acids will markedly decrease glucose metabolism in the heart. These high levels of fatty acids occur in most clinically relevant conditions of myocardial ischemia, and can contribute to the severity of ischemic injury. A number of pharmacologic agents are now available that directly stimulate myocardial glucose metabolism or indirectly stimulate glucose metabolism secondary to an inhibition of fatty acid metabolism. One agent that appears to act by this mechanism is trimetazidine, which we recently found stimulates glucose oxidation in isolated rat hearts perfused with high levels of fatty acids. Clinical studies have also shown that trimetazidine has cardioprotective effects in the setting of myocardial ischemia. As a result, optimizing energy metabolism with agents such as trimetazidine may have considerable promise as a new approach to treating cardiovascular disease.