Necrotizing enterocolitis (NEC) has received considerable attention in the past 5 decades, but remains difficult to diagnose and to treat. Barriers in the field include the lack of clear definitions of NEC, the confusion of NEC with other entities, and the questionable relevance of some of the available animal models. Improvements in NEC care will require a systematic, “omics” approach, including a focus on multiple gene pathways and the microbiome.