HPV matches ventilation to perfusion and optimizes systemic oxygenation in the adult and, in the fetus, minimizes flow to the unexpanded lung. In HPV, small, resistance pulmonary arteries (PA) constrict in response to local alveolar hypoxia. This mechanism is conserved across species and is intrinsic to the pulmonary artery smooth muscle cells (PASMC), being strongest in distal PAs (<200µM). The “Redox Hypothesis” defines the mechanism of HPV as a rapid, reversible, redox regulation of K+ channel function1. According to this hypothesis (summarized in 2), HPV is initiated by a mitochondrial O2 -sensor, that regulates production of diffusible redox mediators (reactive O2 species, ROS and redox couples) by the activity of Krebs’ cycle and the electron transport chain. This controls the redox state of the cytosol and ion channels. The production of ROS occurs in proportion to alveolar PO2 (more oxygen=more ROS3). These reactive O2 species (ROS, particularly diffusible hydrogen peroxide) in turn, control the gating of specific K+ channels. Decreased ROS (or a reduced redox state) inhibits K+ channels in PASMC, leading to membrane depolarization, calcium entry via the L-type calcium channel and pulmonary vasoconstriction. Whole cell patch clamp technique directly proved that hypoxia uniquely inhibits K+ channels in PA but not systemic arterial myocytes4. Subsequently, the voltage gated potassium channels (Kv) inhibited by hypoxia (Kv1.5 and Kv2.1) were identified5. Supporting an important role for Kv1.5, HPV and O2-sensitive potassium current are reduced Kv1.5 knockout mice6. Moreover, the preferential occurrence of HPV in resistance PAs relates to their enrichment in the expression of O2-sensitive Kv channels (e.g. Kv1.5, Kv2.1, Kv3.1)7 (as well as the presence of mitochondria that vary ROS production in proportion to PO28). In conditions where HPV is suppressed (chronic hypoxia), Kv gene therapy can restore HPV9. Over the past 2 decades, the redox theory has met with mixed reviews. The K+ channel mechanism is generally accepted and has been reproduced by man labs. O2-sensitive K+ channels are a conserved mechanism in other specialized O2-sensing tissues, such as the carotid and neuroepithelial bodies. However, the specific K+ channels involved are diverse. TASK and trp channels are important to HPV. Moreover, the release of cytosolic calcium and activation of rho kinase also contributes to HPV. Controversies as to the effect of physiologic hypoxia on ROS production are ongoing, although there is increasing consensus that the mitochondria are important O2 sensors and regulate vascular tone through redox regulation of K+ channel gating, which is the essence of the redox hypothesis. This pathway for oxygen-sensing is also relevant to Pulmonary Arterial Hypertension, a condition in which Kv1.5 channel expression is suppressed.