Despite the importance of the pulmonary circulation as a determinant of exercise capacity in health and disease, studies into the regulation of pulmonary vascular tone in the healthy lung during exercise are scarce. This review describes the current knowledge of the role of various endogenous vasoactive mechanisms in the control of pulmonary vascular tone at rest and during exercise. Recent studies demonstrate an important role for endothelial factors (NO and endothelin) and neurohumoral factors (noradrenaline, acetylcholine). Moreover, there is evidence that natriuretic peptides, reactive oxygen species and phosphodiesterase activity can influence resting pulmonary vascular tone, but their role in the control of pulmonary vascular tone during exercise remains to be determined. K-channels are purported end-effectors in control of pulmonary vascular tone. However, K-ATP channels do not contribute to regulation of pulmonary vascular tone, while the role of K-V and K-Ca channels at rest and during exercise remains to be determined. Pulmonary hypertension is associated with alterations in pulmonary vascular function and structure, resulting in blunted pulmonary vasodilatation during exercise and impaired exercise capacity Although there is a paucity of studies pertaining to the regulation of pulmonary vascular tone during exercise in idiopathic pulmonary hypertension, the few studies that have been performed in models of pulmonary hypertension secondary to left ventricular dysfunction suggest altered control of pulmonary vascular tone during exercise. Since the increased pulmonary vascular tone during exercise limits exercise capacity, future studies are needed to investigate the vasomotor mechanisms that are responsible for the blunted exercise-induced pulmonary vasodilatation in pulmonary hypertension. (C) 2008 Elsevier Inc. All rights reserved.