Cardiovascular diseases account for approximately one third of all deaths globally. Obese and diabetic patients have a high likelihood of dying from complications associated with cardiovascular dysfunction. Obesity and diabetes increase circulating lipids that upon tissue uptake, may be stored as triglyceride, or may be metabolized in other pathways, leading to the generation of toxic intermediates. Excess lipid utilization or activation of signaling pathways by lipid metabolites may disrupt cellular homeostasis and contribute to cell death, defining the concept of lipotoxicity. Lipotoxicity occurs in multiple organs, including cardiac and vascular tissues, and a number of specific mechanisms have been proposed to explain lipotoxic tissue injury. In addition, recent data suggests that increased tissue lipids may also be protective in certain contexts. This review will highlight recent progress toward elucidating the relationship between nutrient oversupply, lipotoxicity, and cardiovascular dysfunction. The review will focus in two sections on the vasculature and cardiomyocytes respectively. © Springer Science+Business Media, LLC 2012.