For over 50 years, retinal hypoxia has been considered to be a major causative factor in the development of retinal neovascularization (NV), a condition associated with blindness and vision loss in a variety of retinopathies. Review of the existing literature and results of new experiments from our laboratory strongly suggest that the oxygen-based pathophysiology stimulating retinal NV is more complicated than previously thought. Our evidence identifies at least two independent conditions involved in the pathogenesis of retinal NV: hypoxia measured under steady-state conditions (i.e., static hypoxia) and found at the border of vascular and avascular retina, and subnormal oxygenation response measured during a provocation and found over both vascular and avascular retina. In practical terms, the identification of links between static hypoxia, oxygen supply dysfunction and NV may lead to improved therapeutic strategies for preventing vision loss and blindness from retinal NV.