Retinal neovascularization is a serious complication of the retinopathy associated with diabetes, branch vein occlusion, sickle cell anemia, and retrolental fibroplasia. Retinal capillary nonperfusion, demonstrated on fluorescein angiography, precedes the development of neovascularization in each of these conditions. Our working hypothesis is that the nonperfused (ischemic or hypoxic) retina liberates a vasoproliferative or angiogenic substance. Although I have delineated the clinical and experimental observations relating to the hypothesis of an ischemic-mediated angiogenesis substance, other postulated mechanisms for the development of retinal neovascularization may be involved. Recent observations on the experimental model of retrolental fibroplasia have demonstrated the markedly abnormal persistence and apparent proliferation of the hyaloid vessels in mice following oxygen-induced retinal vascular closure.