Excess fatty acid accumulation in nonadipose tissues is a hallmark of metabolic disease. When elevated lipid levels exceed the cell's capacity to store or utilize fatty acids, a lipotoxic-response is elicited, characterized by destruction of organelle membranes, activation of stress pathways, and apoptosis. This Minireview focuses on the mechanisms by which lipid overload causes nonadipose cell death and contributes to the pathogenesis of obesity and diabetes.