Ambrisentan, an orally active, highly selective antagonist of the endothelin-1 type A receptor, is indicated for the treatment of pulmonary arterial hypertension (PAH). It has a low potential for drug-drug interactions and requires only once-daily administration. Three months' treatment with ambrisentan 2.5-10 mg/day significantly improved exercise capacity, as determined by the distance walked in 6 minutes (6MWD; primary outcome measure), compared with placebo in two double-blind, multicenter studies in patients with PAH (ARIES-1 [n = 202] and -2 [n = 192]). A decrease in dyspnea and a delay in clinical worsening were among the improvements in secondary outcomes generally observed with ambrisentan versus placebo. In ARIES-E, a 2-year extension of ARIES-1 and -2, approved dosages of ambrisentan (5 and 10 mg/day) were associated with a sustained improvement in 6MWD, a generally sustained improvement in dyspnea, and a low risk of clinical worsening and of death. Six months' treatment with ambrisentan 5 mg/day significantly improved 6MWD (primary outcome measure) and dyspnea relative to baseline in an open-label, non-comparative, multicenter study in a diverse population of patients with PAH or non-PAH forms of pulmonary hypertension (ARIES-3 [n = 224]). Ambrisentan was associated with a low risk of clinical worsening and of death. Ambrisentan treatment was generally well tolerated in the various ARIES trials. All available pre-registration and post-marketing data indicate the drug poses only a very low risk of liver injury; the 'black box' warning regarding potential liver injury has been removed from the US prescribing information for ambrisentan.