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The Redox Theory for the mechanism of HPV proposes the coordinated action of a redox sensor (the proximal mitochondrial electron transport chain) that generates a diffusible mediator [a reactive O<jats:sub>2<\/jats:sub>species (ROS)] that regulates an effector protein [voltage-gated potassium (K<jats:sub>v<\/jats:sub>) and calcium channels]. A similar mechanism for regulating O<jats:sub>2<\/jats:sub>uptake\/distribution is partially recapitulated in simpler organisms and in the other specialized mammalian O<jats:sub>2<\/jats:sub>-sensitive tissues, including the carotid body and ductus arteriosus. Inhibition of O<jats:sub>2<\/jats:sub>-sensitive K<jats:sub>v<\/jats:sub>channels, particularly K<jats:sub>v<\/jats:sub>1.5 and K<jats:sub>v<\/jats:sub>2.1, depolarizes pulmonary artery SMCs, activating voltage-gated Ca<jats:sup>2+<\/jats:sup>channels and causing Ca<jats:sup>2+<\/jats:sup>influx and vasoconstriction. Downstream of this pathway, there is important regulation of the contractile apparatus' sensitivity to calcium by rho kinase. Controversy remains as to whether hypoxia decreases or increases ROS and which electron transport chain complex generates the ROS (I and\/or III). Possible roles for cyclic adenosine diphosphate ribose and an unidentified endothelial constricting factor are also proposed by some groups. Modulation of HPV has therapeutic relevance to cor pulmonale, high-altitude pulmonary edema, and sleep apnea. 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