Epoprostenol was the first therapy to be approved for the treatment of pulmonary arterial hypertension (PAH). In the 20 years since the introduction of this prostacyclin analogue, the outlook for patients with PAH has improved, with survival rates now double those from the era before the development of disease-specific treatments. Today, there are a large amount of data on the clinical role of prostacyclin treatments and a body of evidence attesting the efficacy of epoprostenol in improving exercise capacity, key haemodynamic parameters and PAH symptoms, as well as in reducing mortality. The place of epoprostenol in the therapeutic management of PAH continues to evolve, with the development of new formulations and use in combination with other drug classes. In this review, we provide a historical perspective on the first 20 years of epoprostenol, a therapy that led to evidence-based study of PAH-specific treatments and the subsequent expansion of treatment options for PAH.