Necrotizing enterocolitis (NEC) has largely been present in neonatal intensive care units for the past 60 years. NEC prevalence has corresponded with the continued development and sophistication of neonatal intensive care. Despite major efforts towards its eradication, NEC has persisted and appears to be increasing in some centers. The pathophysiology of this disease remains poorly understood. Several issues have hampered our quest to develop a better understanding of this disease. These include the fact that what we have historically termed 'NEC' appears to be several different diseases. Animal models that are commonly used to study NEC pathophysiology and treatment do not directly reflect the most common form of the disease seen in human infants. The pathophysiology appears to be multifactorial, reflecting several different pathways to intestinal necrosis with different inciting factors. Spontaneous intestinal perforations, ischemic bowel disease secondary to cardiac anomalies as well as other entities that are clearly different from the most common form of NEC seen in preterm infants have been put into the same database. Here I describe some of the different forms of what has been called NEC and make some comments on its pathophysiology, where available studies suggest involvement of genetic factors, intestinal immaturity, hemodynamic instability, inflammation and a dysbiotic microbial ecology. Currently utilized approaches for the diagnosis of NEC are presented and innovative technologies for the development of diagnostic and predictive biomarkers are described. Predictions for future strategies are also discussed.