Hypoxic vasoconstriction is unique to pulmonary circulation. The pulmonary response is part of a self-regulatory mechanism by which pulmonary capillary blood flow is automatically adjusted to alveolar ventilation for maintaining the optimal balance of ventilation and perfusion. In pathological conditions, hypoxic pulmonary vasoconstriction may occur as an acute episode or as a sustained response with pulmonary hypertension and vascular remodeling. Vasoactive substances produced from the endothelial cells (prostanoids, nitric oxide, or endothelin) or other mediators such as 5 hydroxytryptamine have been examined as possible mediators of hypoxic vasoconstriction. These appear more likely to be modulators than mediators of the vasoconstrictor response to hypoxia. Recent hypotheses have emerged indicating that O2 levels per se can regulate ion channel activity. The modulation of both K+ and Ca2+ channels differs according to the conduit or resistance pulmonary vessel type, tending to extend the former and contract the latter, thereby opposing the ventilation to perfusion mismatching. In the absence of drugs that act selectively on pulmonary circulation, inhaled therapy is an alternative in the treatment of pulmonary hypertension. According to its short half-life and to its potential cytotoxicity, nitric oxide is only of value in the management of patients with acute respiratory disease. Aerosolized prostacyclin and iloprost result in a sustained efficacy of the inhaled vasodilator regimen in patients with severe pulmonary hypertension and offer a new strategy for treatment of this disease. At the moment, therapy aimed at reversing the structural remodeling and matrix deposition in pulmonary arteries remains experimental. New drugs such as potassium channel openers or endothelin receptor antagonists warrant further investigations as possible therapeutic candidates in the treatment of pulmonary hypertension.