Hypoxic pulmonary vasoconstriction is postulated to be an adaptive mechanism to match lung perfusion with ventilation; however, the consequences of the maladaptive effects of pulmonary vasoconstriction represent formidable therapeutic challenges. Understanding the basic mechanisms of hypoxic pulmonary vasoconstriction will enhance the assimilation of translational research into clinical practice. The purposes of this review are to (1) define basic mechanisms of pulmonary vasoconstriction and vasorelaxation; (2) delineate the biphasic contractile response to hypoxia; (3) critically examine data that support the mediator hypothesis versus the ion channel hypothesis; and (4) explore potential mechanistic-based therapies for hypoxic pulmonary vasoconstriction.