Necrotizing enterocolitis (NEC) is the most common life-threatening gastrointestinal emergency encountered in the neonatal intensive care unit. Despite advances in neonatal care, NEC remains a leading cause of morbidity and mortality among premature infants. Epidemiologic studies have identified multiple factors that increase an infant's risk for the development of NEC, although premature birth, bacterial colonization, and enteral feeding are thought to play central roles in disease pathogenesis. Appreciating factors that underlie the susceptibility of prematurely born infants to NEC is important for the development of new strategies aimed at the prevention and treatment of disease. In this review, we discuss defense mechanisms in the intestine and discuss how these systems may be insufficient in the prematurely born infant and thereby further contribute to initiation of NEC. In addition, based on a review of the literature, we suggest that, although numerous bacterial and viral pathogens have been associated with NEC, no individual organism is known to be responsible for disease. Finally, we comment on the possible role for probiotics in promoting maturation of intestinal defense mechanisms thereby attenuating or preventing the sequence of events that lead to NEC.