The etio-pathogenesis of necrotizing enterocolitis (NEC) is complex and multifactorial. Decades of research have not identified a definite etiology. Prematurity, enteral feeding, intestinal hypoxia/ischemia, inflammation and an abnormal microbiome are potential risk factors for developing this multisystem illness. Lack of specific diagnostic and prognostic markers adds to the challenges faced in managing NEC. Vascular mediators such as Nitric oxide (NO), catecholamines and endothelin (ET) regulate neonatal intestinal vascular resistance and may influence the pathophysiology of NEC. Neonatal morbidities, medications, transfusions, an altered microbiome and breast milk feeds may influence the vasculature in various ways. Better understanding of these mediators and their role in regulation of intestinal microcirculation and pathogenesis of NEC will assist in identifying strategies in prevention and management of this devastating illness.