Progression of ischemic retinal diseases, such as diabetic retinopathy, is closely associated with pathological retinal angiogenesis mainly induced by vascular endothelial growth factor (VEGF). Anti-angiogenic therapy using anti-VEGF antibodies is effective in treating diabetic retinopathy, even though its efficacy is not long-lasting. Since many factors are involved in angiogenesis, it is reasonable to seek new therapeutic target molecules in pathological retinal angiogenesis. We have found that apelin/APJ system is involved in not only physiological but also pathological retinal angiogenesis using a mouse model of oxygen-induced retinopathy (OIR). Oxygen-induced vessel loss in the retinas of OIR model leads to a significant increase in the capillary density accompanied by abnormal vessel growth, similar to aneurysms, which are hardly detected in the retinas of control mice. Compared with age-matched control mice, retinal apelin expression was dramatically increased during retinal angiogenesis in OIR model. Immunostaining for APJ, apelin receptor, in retinal from OIR model revealed that APJ was localized in proliferating endothelial cells in the retinal vascular plexus. Retinal angiogenesis in the OIR model was rarely observed in apelin deficient mice, although temporal expression pattern of VEGF was similar to that of wild-type OIR model. In addition, clinical study showed that vitreous concentrations of apelin were significantly higher in the proliferative diabetic retinopathy group than in the control group. Taken together, these findings clearly suggest that apelin/APJ system may be a crucial factor for pathological retinal angiogenesis. Inhibition of this system could offer new therapeutic opportunities against ischemic retinopathy.