Accumulation of long-chain fatty acids in the heart has been proposed to play a role in the development of heart failure and diabetic cardiomyopathy. Several animal models with increased cardiomyocyte lipid accumulation suggest a link between the accumulation of lipid, cardiomyocyte cell death and the development of cardiomyopathy. In this review, we discuss the mechanism through which fatty acid accumulation may contribute to the development or progression of heart failure by initiation of apoptotic cell death. Long-chain saturated fatty acids induce apoptosis through a mechanism involving the generation of reactive intermediates. Reactive intermediate production occurs in concert with de novo ceramide synthesis, but ceramide production is not required for cell death. Cardiomyocyte dysfunction and death from reactive intermediates generated by long-chain saturated fatty acids may contribute to the pathogenesis of human heart disease.