AbstractAlterations in cardiac energy metabolism are an important contributor to the high incidence and severity of heart disease in the world. These alterations can include an impairment of the production of ATP necessary to meet the high energy demands of the heart, as well as adverse switches in energy substrate preference by the heart. With regard to this latter point, evidence suggests that a decrease in cardiac efficiency, caused by a rise in cardiac fatty acid oxidation and/or an increase in the uncoupling of glycolysis from glucose oxidation, impairs cardiac function and is a contributing factor to cardiac disease. In support of this concept, therapeutic strategies that modulate these metabolic pathways and increase cardiac efficiency produce beneficial results in the setting of heart disease. One such strategy is to increase cardiac malonyl CoA levels, an important inhibitor of mitochondrial fatty acid uptake. This includes malonyl CoA decarboxylase (MCD) inhibition that results in increased cardiac malonyl CoA levels, decreased cardiac fatty acid oxidation rates, and improved cardiac efficiency. Preclinical studies have shown that MCD inhibition can improve cardiac function in various forms of heart disease. Here, we focus on the importance of malonyl CoA in the regulation of cardiac energy metabolism and function in the normal and diseased heart and discuss the evidence that suggests that inhibition of fatty acid oxidation especially via regulation of malonyl CoA, through MCD inhibition, is a promising strategy to treat cardiac disease. © 2014 IUBMB Life, 66(3):139–146, 2014