Pathological conditions associated with retinal hypoxia promote local neovascularization, which can lead to blindness; indeed, ischemic proliferative retinopathies are leading causes of blindness in children and during middle age. Noting that citric acid cycle intermediates can accumulate when oxygen supply is inadequate, Sapieha et al. explored the role of succinate, which signals through G protein-coupled receptor-91 (GPCR91), in mediating retinal angiogenesis. Succinate abundance was increased in the ischemic retinas of young rats [elicited through oxygen-induced retinopathy (OIR)], whereas the abundance of GPCR91 mRNA and protein [predominantly localized in retinal ganglion cells (RGCs)] was unaffected. Intravitreal injection of siRNA directed against GPCR91 on postnatal day 1 decreased developmental retinal vascularization and blood vessel density, as did retinal infection with lentivirus shRNA targeting GPCR91, whereas succinate had the opposite effect. Conditioned medium from cultured RGCs that had been treated with succinate stimulated vascular sprouting from aortic explants, as did coculture with succinate-primed RGCs, effects that were inhibited by GPCR91 knockdown. Intravitreal injection of succinate increased RGC expression of the mRNA encoding the proangiogenic factors VEGF, angiopoietin-1, and angiopoietin-2 but decreased that of the antiangiogenic thrombospondin-1; again, these effects were inhibited by GPCR91 knockdown. Loss of RGCs in adult rats after optic nerve axotomy abolished stimulation of VEGF expression and angiogenesis by intravitreal succinate. Moreover, transgenic mice lacking RGCs also lacked a retinal vascular plexus. Intriguingly, siRNA directed against GPCR91 decreased pathological vascularization in rats subjected to OIR. The authors conclude that succinate signaling through GPCR91 is critical to retinal vascularization and that GPCR91 may provide a therapeutic target against pathological retinal neovascularization.