A critical question related to the deactivation of mitochondrial metabolism in heart failure is whether such energy metabolic abnormalities contribute to the pathology of, or are secondary to, the pathological remodeling of heart failure. Altered metabolism was originally considered a byproduct of these pathological states. However, emerging evidence, including observations of the phenotypic expression of genetic defects in humans and animal models, supports the notion that derangements in mitochondrial energy metabolism contribute to cardiac dysfunction. For example, human mitochondrial DNA mutations resulting in global impairment in mitochondrial respiratory function cause hypertrophic or dilated cardiomyopathy and cardiac conduction defects. 35–37 Mutations in nuclear genes encoding mitochondrial fatty acid oxydation enzymes may also manifest as cardiomyopathy. 38–41 Interestingly, cardiomyopathies resulting from inborn errors in mitochondrial fatty acid oxydation enzymes are often provoked by physiological or pathophysiological conditions that increase dependence on fat oxidation for myocardial ATP production such as prolonged exercise or fasting associated with infectious illness. 39, 41 A causal relationship between mitochondrial dysfunction and cardiomyopathy also is evidenced by several genetically engineered mouse models. Targeted deletion of the adenine nucleotide translocator 1, which transports mitochondrially generated ATP to the cytosol, leads to mitochondrial dysfunction and cardiomyopathy. 42 Mice with cardiac-specific deletion of transcription factor of activated mitochondria, which controls transcription and replication of the mitochondrial genome, also exhibit marked impairments in mitochondrial metabolism, severe cardiomyopathy, and premature mortality. 43 Cardiomyopathy and/or conduction defects also are observed in several mouse models with targeted deletion of specific FAO enzymes. 44–46 Taken together, the cardiac phenotype caused by genetic defects in mitochondrial energy transduction or ATP production in humans and mice provides proof of concept for causal links between derangements in mitochondrial energy metabolism and cardiac dysfunction.