Cardiomyopathy is associated with both rare genetic metabolic abnormalities and highly prevalent diseases characterized by elevated serum triglycerides and nonesterified fatty acids, such as obesity and type 2 diabetes. In these disorders, an imbalance between fatty acid uptake and utilization leads to the inappropriate accumulation of free fatty acids and neutral lipids within cardiomyocytes. Through the process of lipotoxicity, this lipid overload causes cellular dysfunction, cell death, and eventual organ dysfunction. This review focuses on lipotoxicity in the heart, with an emphasis on the contribution of this process to the pathogenesis of cardiomyopathy associated with obesity, diabetes, and the metabolic syndrome. The magnitude of the current worldwide epidemic of obesity and type 2 diabetes suggests that understanding the pathogenesis of cardiac complications associated with these diseases will contribute substantially to improvements in health care.