Necrotizing enterocolitis (NEC) is a catastrophic inflammatory bowel necrosis of premature infants. The etiology is unknown, but 25-40 % of cases have a history of red blood cell (RBC) transfusions in the preceding 48 h. This association has been noted in retrospective case/case-control studies, and many meta-analyses, and in a murine model. However, we still need human studies with larger, adequately powered cohorts to confirm this association and determine the operant mechanisms. The murine model shows that severe anemia leads to macrophage infiltration in the gut mucosa. Subsequent RBC transfusions containing free hemoglobin, activate nuclear factor-kappa B-mediated inflammatory changes and cause NEC-like mucosal injury. This review summarizes current human and experimental data to evaluate ta-NEC and hitherto unanswered mechanistic questions. If a causal relationship between transfusions and NEC is proven, these data could help develop effective therapeutic strategies.