Retinopathy of prematurity (ROP) is a major cause of blindness in children in developed countries. ROP, a two-phase disease, is initiated with delayed retinal vascular growth after premature birth (phase I). Insufficient vascularization of the developing retina creates hypoxia, which precipitates the release of factors stimulating new and abnormal blood vessel growth (phase II). ROP develops because of abnormalities in both oxygen-regulated and non-oxygen-regulated factors, which affect both phases of the disease. Vascular endothelial growth factor (VEGF) is an important oxygen-regulated factor that, if suppressed, inhibits normal vessel growth, but in excess, precipitates retinal neovascularization. A critical non-oxygen-regulated growth factor is insulin-like growth factor (IGF-1). Similar to VEGF, low levels of IGF-1 prevent normal vessel growth (phase I), and higher levels allow neovascularization (phase II). We found that premature infants who develop ROP have low levels of serum IGF-1 compared with age-matched infants without disease. IGF-1 is critical to normal vascular development. Low IGF-1 predicts ROP, and restoration of IGF-1 to normal levels might prevent ROP.