The intestinal mucosa functions as a major local defense barrier preventing bacteria that colonize the gut from invading organs and tissues. Under certain circumstances, bacteria colonizing the gastrointestinal tract can cross the gut mucosal barrier to infect the mesenteric lymph node and systemic organs via a process termed bacterial translocation. Factors that promote the translocation of bacteria or endotoxin from the gut include bacterial overgrowth with gram-negative enteric bacilli, impaired host immune defenses and injury to the gut mucosa resulting in increased intestinal permeability. These same promoting factors are present in patients at increased risk of developing necrotizing enterocolitis. Consequently, this review focuses on the potential role of bacterial and endotoxin translocation from the gut in the pathogenesis of necrotizing enterocolitis.