Although necrotizing enterocolitis (NEC) is the most lethal gastrointestinal disease in the neonatal population, its pathogenesis is poorly understood. Risk factors include prematurity, bacterial colonization, and formula feeding. This review examines how mucosal injury permits opportunistic pathogens to breach the gut barrier and incite an inflammatory response that leads to sustained overproduction of mediators such as nitric oxide and its potent adduct, peroxynitrite. These mediators not only exacerbate the initial mucosal injury, but they also suppress the intestinal repair mechanisms, which further compromises the gut barrier and culminates in bacterial translocation, sepsis, and full-blown NEC.