Necrotizing enterocolitis (NEC) is a leading cause of morbidity and mortality among infants in the neonatal intensive care unit. Here we review the epidemiology and pathophysiology of NEC, with an emphasis on the latest research findings and potential areas for future research. NEC continues to be one of the most devastating and unpredictable diseases affecting premature infants. Despite decades of research, the pathogenesis of this disease remains unclear, and prevention and treatment strategies are limited. Hopefully, future studies aimed at understanding premature intestinal defenses, commensal or probiotic bacterial influences, and possible genetic predisposition will lead to the improvement of prevention and treatment strategies.