Hormone refractory prostate cancer remains true to its middle name: it is largely refractory to attempts to delay its progression. New targets and new therapies are demanded. Through a review of the available literature on endothelin and several preclinical observations, the endothelin axis has emerged as one such target. In phase II and III clinical trials of atrasentan, a potent and selective endothelin receptor A subtype (ET(A)) antagonist, disease progression was delayed in some men. This well tolerated, oral agent may help convert advanced prostate cancer to a more chronic disease. This review will discuss the endothelin axis, preclinical rationale and some of the available clinical trial data on this promising new approach.