Necrotizing enterocolitis (NEC) is a significant cause of mortality and morbidity in preterm infants. The pathogenesis of NEC is not completely understood; however, intestinal immaturity and excessive immunoreactivity of intestinal mucosa to in-traluminal microbes and nutrients appear to have critical roles. Dietary fats are not only the main source of energy for preterm infants, but also exert potent effects on intestinal development, intestinal microbial colonization, immune function, and in-flammatory response. Preterm infants have a relatively low capacity to digest and absorb triglyceride fat. Fat may thereby accumulate in the ileum and contribute to the development of NEC by inducing oxidative stress and inflammation. Some fat components, such as long chain polyunsaturated fatty acids (LC-PUFAs), also exert immunomodulatory roles during the early postnatal period when the immune sys-tem is rapidly developing. LC-PUFAs may have the ability to modulate the inflam-matory process of NEC, particularly when the balance between n3 and n6 LC-PUFAs derivatives is maintained. In this review, we describe how various fatty acids play different roles in the pathogenesis of NEC in preterm infants.