Tumor necrosis factor-alpha (TNF alpha) is a proinflammatory cytokine with negative inotropic effects. Recently, elevated levels of TNF alpha have been identified in patients with advanced heart failure. Although the clinical significance of this finding is unclear at present, there is increasing evidence that this cytokine may play a primary pathophysiologic role in the development and pathogenesis of heart failure in humans. Indeed, many of the clinical hallmarks of heart failure, including left ventricular dysfunction, cardiomyopathy, and pulmonary edema can be explained by the known biological effects of TNF alpha in humans. The present review will summarize recent evidence with regard to the biological role for TNF alpha in the adult mammalian heart, as well as summarize the increasing body of clinical information that implicates this cytokine in the pathophysiology of heart failure.