The pathogenesis of necrotizing enterocolitis (NEC) is poorly understood, but appears to be multifactorial and highly associated with immaturity of the gastrointestinal tract, colonization of the intestinal microbiota, and immature innate immune system. The goal of this review is to provide an overview of some of these risk factors and how they might lead to the genesis of NEC. A better understanding of these factors should help us prevent and treat this devastating disease.