Within five years of discovering endothelin (ET-1) in 1988, the first report of an orally available ET receptor antagonist was published. Within twelve years, bosentan, the first ET receptor antagonist to gain marketing authorization, was made available for the treatment of pulmonary artery hypertension (PAH). Since this milestone in ET biology, several ET receptor antagonists have been developed, principally to target cardiovascular disease states. ET-1 acts through two receptors--ET(A) and ET(B). Currently, the mixed antagonist, bosentan, and the selective ET(A) antagonist, sitaxsentan, are both licensed for the treatment of PAH, and clinical trials with these and other agents are ongoing for many diseases, including scleroderma, diabetic nephropathy and prostate cancer. Although there has been no argument about the importance of blocking ET(A) receptors, there remains a long-running debate as to whether additional ET(B) antagonism is of benefit, and this is the topic of the following review.