Myocardial function depends on adenosine triphosphate (ATP) supplied by oxidation of several substrates. In the adult heart, this energy is obtained primarily from fatty acid oxidation through oxidative phosphorylation. However, the energy source may change depending on several factors such as substrate availability, energy demands, oxygen supply, and metabolic condition of the individual. Surprisingly, the role of energy metabolism in development of cardiac diseases has not been extensively studied. For instance, alterations in glucose oxidation and transport developed in diabetic heart may compromise myocardial performance under conditions in which ATP provided by glycolysis is relevant, such as in ischemia and reperfusion. In some cardiac diseases such as ischemic cardiomyopathy, heart failure, hypertrophy, and dilated cardiomyopathy, ATP generation is diminished by derangement of fatty acid delivery to mitochondria and by alteration of certain key enzymes of energy metabolism. Shortage of some co-factors such as L-carnitine and creatine also leads to energy depletion. Creatine kinase system and other mitochondrial enzymes are also affected. Initial attempts to modulate cardiac energy metabolism by use of drugs or supplements as a therapeutic approach to heart disease are described.