Necrotizing enterocolitis (NEC) is a common devastating disease of premature neonates characterized by intestinal tissue inflammation and necrosis and hampered with high morbidity and mortality. While the pathogenesis of NEC remains unclear, several factors may play a role in its pathogenesis: 1) the immaturity of the intestinal barrier, 2) the abnormal bacterial colonization of the premature intestine that triggers a mucosal proinflammatory response, 3) the immature immune system unable to prevent epithelial microbial invasion, and 4) The insufficient substrate and O2 delivery to intestinal epithelial cells due to either incomplete development of the intestinal microvasculature or inability to regulate vascular tone. Interestingly, conditions that predispose the intestine to ischemia, such as congenital heart disease, maternal preeclampsia with placental vascular insufficiency, severe anemia, and blood transfusion, predispose infants to NEC. Our lab recently found that defective vascular endothelial growth factor receptor 2 (VEGFR2) signaling pathway and maldevelopment of the intestinal microvasculature play an important role in NEC pathogenesis. In this chapter, a role for perturbations of intestinal blood flow and defective development of the intestinal mucosal microvasculature in NEC are discussed.