Necrotizing enterocolitis (NEC) is the most common surgical emergency in premature infants. The underlying etiology of NEC remains unknown, although bacterial colonization of the gut, formula feeding, and perinatal stress have been implicated as putative risk factors. The disease is characterized by exuberant gut inflammation leading to ischemia and coagulation necrosis of the intestinal epithelium. The molecular and cellular mechanisms responsible for these pathologic changes are poorly understood. It has been shown that various exogenous and endogenous mediators such as lipopolysaccharide, inflammatory cytokines, platelet activating factor, and nitric oxide may play a role in the pathogenesis of NEC. Recent studies in our laboratory and others have established a link between NEC and activation of cyclooxygenase-2, the enzyme that catalyzes the rate-limiting step in the biosynthesis of prostanoids. The challenge is in defining the molecular signaling pathways leading to accumulation of these mediators early in the disease progression, before the onset of tissue necrosis and systemic sepsis. Identification and characterization of these pathways could lead to the development of novel treatment strategies to alleviate the morbidity and mortality associated with NEC.