Chronic pressure overload and atherosclerosis are primary etiologic factors for cardiac hypertrophy and failure. However, mechanisms underlying the transition from hypertrophy to heart failure are incompletely understood. We analyzed the development of heart failure in mice with chronic pressure overload induced by aortic constriction and compared the results with aged apolipoprotein E-deficient mice suffering from advanced atherosclerosis. We combined cardiac function analysis by echocardiography and invasive hemodynamics with a comprehensive microarray gene expression study (GSE25765-8). The microarray data showed that the onset of heart failure induced by pressure overload or advanced atherosclerosis was accompanied by a strong up-regulation of key lipid metabolizing enzymes involved in fat synthesis, storage and oxidation. Cardiac lipid overload may be involved in the progression of heart failure by enhancing cardiomyocyte death. Up-regulation of the cardiac lipid metabolism was related to oxygen and ATP depletion of failing hearts because anti-ischemic treatment with ranolazine normalized the cardiac lipid metabolism and improved cardiac function. Vice versa, inhibition of cellular respiration and ATP generation by mild thiol-blocking with cystamine triggered the cardiac lipid metabolism and caused signs of heart failure. Cardiac tissue specimens of patients with heart failure also showed high protein levels of key fat metabolizing enzymes as well as lipid accumulation. Taken together, our data strongly indicate that up-regulation of the cardiac lipid metabolism and myocardial lipid overload are underlying the development of heart failure.