Ischemic heart disease is characterized by a modification of the normal energy balance of the heart. During and following an ischemic event, circulating fatty acids are elevated, resulting in the acceleration of fatty acid oxidation at the expense of glucose oxidation. Despite the reduction in glucose oxidation, the rate of glycolysis increases, leading to an uncoupling of glucose metabolism. This results in the accumulation of metabolic byproducts, which leads to a decrease in cardiac efficiency. A novel therapeutic strategy involves improving the efficiency of oxygen utilization by the ischemic heart by the modulation of energy metabolism. This can be achieved by a reduction in the levels of circulating fatty acids using beta-blockers, glucose-insulin-potassium infusions, and nicotinic acid. Alternatively, fatty acid oxidation can be directly inhibited using trimetazidine, ranolazine, or glucose oxidation directly activated using dichloroacetate, which significantly improves the efficiency of the heart.