Physiological hypoxia results in a host of responses that include increased ventilation, constriction of the pulmonary artery, and a cellular transcriptional program that promotes glycolysis, angiogenesis, and erythropoiesis. Mitochondria are the primary consumers of cellular oxygen and have thus been speculated for years to be the site of cellular oxygen sensing. Many of the cellular responses to hypoxia are now known to be mediated by the production of reactive oxygen species at mitochondrial complex III. While the mechanism by which cytosolic oxidant concentration is increased during hypoxia is unknown, the importance of the maintenance of cellular oxygen supply requires further investigation into the role of ROS as hypoxia signaling molecules. The following is a brief overview of the current understanding of the role of mitochondrial-produced ROS in cellular oxygen signaling.