The vasodilator effect of acetylcholine on the pulmonary circulation was first described over 30 years ago, however, the mechanism remained unknown until Furchgott described the endothelium-dependent relaxation of certain vasodilators. It was not until 1987 that endothelium-derived relaxant factor (EDRF) was demonstrated to dilate human pulmonary arteries in vitro. Despite this work, the physiologic role of EDRF in the pulmonary circulation is not known. It has been suggested that hypoxia-induced inhibition of EDRF action or release from pulmonary artery endothelial cells may have a role in hypoxic pulmonary vasoconstriction (HPV) but present evidence suggests that loss of EDRF activity is not directly involved in the phenomenon of HPV. It is more likely that EDRF is released from pulmonary artery endothelial cells during hypoxia and this released EDRF then modulates HPV. If EDRF does modulate HPV in vivo then the role of EDRF in the altered HPV found in disease merits attention. It is known that in disease states such as acute lung injury and pneumonia there is loss or attenuation of HPV which inevitably leads to increased V/Q mismatch and hypoxemia. Whether this attenuation of HPV is due to release of an endogenous vasodilator such as EDRF is presently being investigated. Additionally, there is in vitro evidence that loss of EDRF activity may be important in the genesis of pulmonary hypertension such as found in severe cystic fibrosis. During the next decade the role of EDRF in the human pulmonary circulation in both health and disease will undoubtedly be elucidated.