The discovery of endothelin — a highly potent endogenous vasoconstrictor — in 1988 has led to considerable efforts to develop antagonists of endothelin receptors that could have therapeutic potential in disorders including hypertension, heart failure and renal diseases. However, in general, the results of trials in humans have not mirrored the highly promising effects in animal disease models. Here, we discuss preclinical and clinical results with endothelin antagonists, and consider possible approaches to fully realizing the potential of endothelin antagonism.