The endothelium produces several vasodilating factors such as prostacyclin or nitric oxide and also vasoconstricting agents such as endothelin. These factors play an important role in the regulation of vascular tone and tissue perfusion. Several recent studies have evaluated the role of endothelin and NO in the pathophysiology of congestive heart failure. This paper reviews the data suggesting that endothelin and NO contribute to the neuro-hormonal compensatory mechanisms in patients with heart failure and that specific blockade of endothelin receptors could be an effective new approach for the treatment of patients with severe congestive heart failure.