Macitentan (Opsumit®) is a novel dual endothelin receptor antagonist (ERA) with sustained receptor binding properties developed by Actelion Pharmaceuticals Ltd. In October 2013, oral macitentan 10 mg once daily received its first global approval in the US, followed closely by Canada, for the treatment of pulmonary arterial hypertension (PAH). The drug has also received a positive opinion in the EU from the Committee for Medicinal Products for Human Use for the treatment of PAH, and is under regulatory review in several other countries for the same indication. Endothelin (ET)-1 influences pathological changes via two ET receptor subtypes (ETA and ETB), to which it binds with high affinity. ET-1 is implicated in several forms of vascular disease making it a valid target for the treatment of pulmonary vascular diseases such as PAH. Clinical development is underway for other indications, including Eisenmenger syndrome, ischaemic digital ulcers secondary to systemic sclerosis, and glioblastoma. Macitentan was also evaluated in idiopathic pulmonary fibrosis; however, a phase 2 trial did not meet its primary endpoint and further investigation in this indication was discontinued. Macitentan was developed by modifying the structure of bosentan in the search for an optimal dual ERA with improved efficacy and tolerability compared with other ERAs. This article summarizes the milestones in the development of macitentan leading to this first approval for PAH.