Progress in our understanding of the pathophysiology, prevention and treatment of necrotizing enterocolitis (NEC) has been hampered for many reasons. Included among these is the fact that what we are calling “NEC” is likely to represent different disease processes, which need to be delineated before evaluating individual pathogenic mechanisms and attempting to develop predictive and diagnostic biomarkers. Treatment is also likely to be hampered because not all of the different entities called “NEC” will respond to the same regimen. In this review, some of these entities will be discussed in more detail, with suggestions for refining our approach toward improving methods for their diagnosis, prevention and treatment.