The energy demands of the heart are normally met by oxidation of both glucose and fatty acids. Fatty acid oxidation is limited by the uptake of fatty acyl coenzyme A (CoA) into the mitochondria, a process regulated by carnitine palmitoyltransferase (CPT)1. Malonyl CoA is a potent endogenous inhibitor of CPT1, and therefore plays an integral role in the control of myocardial fatty acid oxidation. Malonyl-CoA decarboxylase (MCD) is responsible for the removal of malonyl CoA and may control myocardial fatty acid oxidation. Indeed, strategies using MCD inhibitors and MCD knockout mice have provided the first evidence for a direct role of MCD in the control of myocardial fatty acid oxidation. Based on these studies, pharmacologic inhibition of MCD has been proposed to be a viable approach for the treatment of ischemic heart disease resulting from a variety of pathologic conditions, including coronary artery diseases, pathologic hypertrophy, and hypertension.