Endothelin-1 (ET-1) is a potent molecule produced throughout the cardiovascular system; it can exert important effects on both the structure and function of vascular smooth muscle cells and cardiac myocytes. ET-1 appears to play a central role in the physiological regulation of cardiovascular function, particularly in the vasculature. The known actions of ET-1 and the demonstration that plasma ET-1 is elevated in patients with heart failure has raised the possibility that this molecule could play a role in the pathophysiology of heart failure. This thesis has been supported and furthered by studies in animal models of heart failure that demonstrate the salutary, short-term effects of ET-1 receptor antagonists on hemodynamic function, as well as improved ventricular remodeling and survival with long-term administration. Early clinical trials with these ET receptor blockers have demonstrated systemic vasodilation. Long-term trials to determine the effects of ET-1 blockade on symptoms and survival are under way.