The endothelin (ET) axis represents a novel and exciting target in the treatment of prostate cancer. ET-1, acting primarily through the endothelin A receptor (ET(A)), is integrally involved in multiple facets of prostate cancer progression, including cell growth, inhibition of apoptosis, angiogenesis, development and progression of bone metastases, and mediation of pain responses. Clinical trials with the ET(A) antagonist, atrasentan, have demonstrated good tolerability, with the most common adverse events being headache, rhinitis, and peripheral edema. These trials have demonstrated statistically significant improvements in pain measures, prostate-specific antigen (PSA) kinetics, biologic markers of bone changes, and development of bone metastases. There have also been consistent improvements in time to progression, although not always statistically significant. Ongoing studies in a variety of patient populations will better define the role of ET receptor antagonists in the treatment of men with prostate cancer. In this article, we review the biology and pathophysiology of the ET axis in prostate cancer, critically analyze the major clinical trials reported to date, and discuss some emerging data and how it may impact the way we proceed in the future with the development of this class of drugs in prostate cancer.