Macitentan (ACT-064992), under development by Actelion Ltd in collaboration with Japanese licensee Nippon Shinyaku Co Ltd, is an orally active, non-peptide dual endothelin (ET)(A) and ET(B) receptor antagonist for the potential treatment of idiopathic pulmonary fibrosis (IPF) and pulmonary arterial hypertension (PAH). Scientific evidence suggests that the ET system may play an important role in the pathobiology of several cardiovascular diseases. A major therapeutic advance for the treatment of patients with PAH and IPF has been the pharmacological control of the activated ET system with ET receptor antagonists. Macitentan, because of its ability to target the tissues and to block both ET(A) and ET(B) receptors, is emerging as a new agent to treat cardiovascular disorders associated with chronic tissue ET system activation. The phase I and II clinical trials conducted to date have demonstrated that macitentan increases plasma levels of ET-1, displays dose-dependent pharmacokinetics, and was well tolerated in healthy volunteers and patients. At the time of publication, a phase II trial in patients with IPF and a phase III trial in patients with PAH was ongoing. It is expected that the results of these trials will validate the safety and efficacy of macitentan.