The availability of potent and orally active nonpeptide endothelin (ET) receptor antagonists has generated a host of information on the pathophysiological role of ET-1 in a number of preclinical models including hypertension, renal failure, heart failure and pulmonary hypertension. Convincing data are available to show that ET-1 receptor antagonists are beneficial in humans as far as reversal of deranged systemic and regional hemodynamics associated with CHF and pulmonary hypertension. As in other disease areas, the issue of whether ET(A)-selective or ET(A/B) antagonists are more suited for CHF treatment remains unresolved. ET(B) receptors may mediate some critical processes in the kidney such as sodium and water excretion in addition to releasing vasodilator substances such as NO and prostacyclin from endothelial cells. In heart failure and chronic renal diseases, preservation of ET(B)-mediated responses in the kidney and pulmonary endothelium might be beneficial. On the other hand, blockade of ET(B)-mediated vasoconstriction, smooth muscle cell proliferation and fibrosis by ET(B) antagonists might be beneficial. In clinical trials so far, the hemodynamic effects of mixed antagonists of ET receptors and ET(A) selective antagonists seem equivalent.