The very potent endogenous vasoconstrictor endothelin was discovered in 1988. We know now that there are three isoforms (1, 2, and 3) and two receptor subtypes (A and B). A whole range of peptide and non-peptide antagonists has been developed, some selective for A or B receptors and others with non-selective A/B antagonistic activity. So far the main application of these agents has been experimental--ie, endothelin blockers are used to throw light on disease mechanisms, most notably cardiovascular and renal. However, the non-selective antagonist bosentan and a few other agents have been studied clinically. Evidence so far from preclinical studies and healthy volunteers and from the limited number of investigations in patients permits a listing of the potential areas of clinical interest. These are mainly cardiovascular (eg, hypertension, cerebrovascular damage, and possibly heart failure) and renal. Clouds on the horizon are the need to show that these new agents are better than existing drugs; the possibility of conflicting actions if mixed A/B antagonists are used; and animal evidence hinting that endothelin blockade during development could be dangerous.