Cardiovascular disease is the major cause of death and disability in the world, with ischemic heart disease accounting for the vast majority of this health problem. Current treatments for ischemic heart disease are primarily aimed at either increasing blood and oxygen supply to the heart or decreasing the heart's oxygen demand. A novel treatment strategy involves increasing the efficiency of oxygen use by the heart. During and following ischemia, the heart can become inefficient in using oxygen, due in part to an excessive use of fatty acids as a source of fuel. One potential strategy to increase cardiac efficiency is to inhibit this use of fatty acid oxidation as a fuel source, while stimulating the use of glucose oxidation as a fuel source, which allows the heart to produce energy more efficiently and reduces the acidosis associated with ischemia/reperfusion, both of which are beneficial to the heart. Malonyl CoA is a potent endogenous inhibitor of cardiac fatty acid oxidation, secondary to inhibition of carnitine palmitoyl transferase-I, the gatekeeper of mitochondrial fatty acid uptake. Malonyl CoA is synthesized in the heart by acetyl CoA carboxylase and degraded by malonyl CoA decarboxylase (MCD). Strategies aimed at increasing cardiac malonyl CoA levels, such as via inhibition of MCD, are associated with a decrease in fatty acid oxidation rates, and a parallel increase in glucose oxidation rates. This is associated with a decrease in acidosis and an improvement in cardiac function and efficiency during and following ischemia. Therefore, targeting malonyl CoA is a novel exciting approach for the treatment of cardiac ischemia/reperfusion.