Elevated endothelin (ET)-1 levels are strongly correlated with the pathogenesis and prognosis of pulmonary arterial hypertension (PAH). Ambrisentan is an orally active, highly selective ETA receptor antagonist with >4000-fold higher selectivity over the ETB receptor. In two large, well designed, 12-week, placebo-controlled, phase III trials (ARIES-1, n = 202 and ARIES-2, n = 192) in patients with PAH (WHO group I), ambrisentan 2.5-10 mg once daily significantly increased 6-minute walk distance by 31-59 m from baseline (primary outcome measure) versus placebo. The incidence of clinical worsening (secondary outcome measure) was significantly delayed for the combined ambrisentan 5 mg once daily groups versus the combined placebo groups from ARIES-1 and -2. At week 12, WHO functional class distribution was significantly improved with once-daily ambrisentan 5 mg, and Borg dyspnoea scores were significantly improved with ambrisentan 2.5-10 mg versus placebo in combined data from the ARIES-1 and -2 trials. The beneficial effects of ambrisentan on exercise capacity, WHO functional class and Borg dyspnoea scores seen at 12 weeks were maintained at 48 weeks in the ARIES-E phase III extension trial (n = 361). One-year survival rates with ambrisentan were 95-97%. Treatment with ambrisentan for up to 2.8 years was generally well tolerated in clinical trials.