Because physicians have traditionally considered heart failure to be a hemodynamic disorder, they have described the syndrome of heart failure using hemodynamic concepts and have designed treatment strategies to correct the hemodynamic derangements of the disease. However, although hemodynamic abnormalities may explain the symptoms of heart failure, they are not sufficient to explain the progression of heart failure and, ultimately, the death of the patient. Therapeutic interventions may improve the hemodynamic status of patients but adversely affect their long-term outcome. These findings have raised questions about the validity of the hemodynamic hypothesis and suggest that alternative mechanisms must play a primary role in advancing the disease process. Several lines of evidence suggest that neurohormonal mechanisms play a central role in the progression of heart failure. Activation of the sympathetic nervous system and renin-angiotensin system exerts a direct deleterious effect on the heart that is independent of the hemodynamic actions of these endogenous mechanisms. Therapeutic interventions that block the effects of these neurohormonal systems favorably alter the natural history of heart failure, and such benefits cannot be explained by the effect of these treatments on cardiac contractility and ejection fraction. Conversely, pharmacologic agents that adversely influence neurohormonal systems in heart failure may increase cardiovascular morbidity and mortality, even though they exert favorable hemodynamic effects. These observations support the formulation of a neurohormonal hypothesis of heart failure and provide the basis for the development of novel therapeutic strategies in the next decade.