The pathobiology of necrotizing enterocolitis (NEC) remains unknown. Immunological, ischemic, endocrine, and infectious mechanisms are thought to be involved in its pathogenesis. Although the primary disease process occurs in the abdomen, the brain is affected as well. An increasing body of evidence supports bidirectional communication between the intestine and the brain through direct and indirect routes. In this chapter, we review the recent clinical and preclinical evidence on NEC-associated brain injury.