Recent data demonstrate the fundamental role of endothelin in the pathogenesis of fibrosis, and the anti-fibrotic potential of dual endothelin receptor antagonists such as bosentan. Although transforming growth factor-beta, aldosterone and connective tissue growth factor, have already been established as contributors to the process of fibrosis, endothelin now emerges as a key player, which may have a role both in the initiation and in maintenance of fibrosis, and may mediate the pro-fibrotic effects of the other agents. Bosentan is an orally active, dual endothelin receptor antagonist, which competitively antagonizes the binding of endothelin to both endothelin receptors ETA and ETB. Bosentan prevents endothelin-induced fibroblast proliferation and extracellular matrix deposition and contraction, and reduces cardiac, hepatic, pulmonary and renal fibrosis in different disease models characterized by the activation of the endothelin system. Bosentan even reverses existing fibrosis, possibly by its effect of stimulating matrix metalloproteinase type 1 (collagenase) expression. The anti-fibrotic effects of bosentan extend to fibrosis induced by mediators other than endothelin such as transforming growth factor-beta, angiotensin II and aldosterone, indicating a central role of endothelin and endothelin receptors in fibrotic processes.