As the population ages, heart failure will continue to be a growing public health problem. Metabolic homeostasis in the heart requires a fine-tuning of metabolism of different substrates. Notwithstanding a retro control of fatty acid and glucose utilization, the heart functions best when it oxidizes both substrates simultaneously. Mismatch between the uptake and oxidation of long-chain fatty acids in the myocardium induces lipotoxicity characterized by the accumulation of triglycerides, diacylglycerols, ceramides and other lipids. Lipotoxicity may result in cardiomyocyte apoptosis, interstitial fibrosis and cardiac dysfunction, and may promote insulin resistance. In this review, we will highlight the impact of lipids and lipoproteins on myocardial biology and on the development of heart failure independent of their effects on coronary heart disease.