Necrotizing enterocolitis (NEC) is a common and devastating disease of premature infants. Immaturity of the innate immune system of the gut is central to the pathogenesis of NEC. Recent studies suggest a key role for Paneth cells in this disease. Addressing basic questions on the development and function of immature Paneth cells may shed light on the puzzling pathophysiology of NEC. Current animal models of NEC are limited in their capacity to answer these questions.