Recently, the mitochondria have become the focus of attention as the site of O2 sensing underlying hypoxic pulmonary vasoconstriction (HPV). From a teleological standpoint, it is reasonable that the organelle where most of the cellular O2 is consumed would also be the site of O2 sensing. Originally, it was proposed that a drop in pO2 decreases the rate of mitochondrial reactive oxygen species (ROS) generation resulting in a decrease in oxidant stress and an accumulation of reducing equivalents, thus causing the inhibition of voltage-dependent K+ channels, membrane depolarization, and the influx of calcium through voltage-gated (L-type) Ca2+ channels. Recently, a new model has emerged that suggests hypoxia triggers a paradoxical increase in a mitochondrial-induced ROS signal. The resulting shift of the cytosol to an oxidized state triggers the release of intracellular Ca2+ stores, recruitment of Ca2+ channels in the plasma membrane, and activation of contraction. Below we will discuss the aspects of this novel model of O2 sensing and its applicability to the HPV response.