The gastrointestinal tract comprises the largest surface area of the human body. This area is constantly exposed to myriad antigens as well as the large number of bacteria that coexist in the intestinal lumen. To protect against this exposure and help distinguish “self ” from “foreign,” the intestinal tract has evolved a sophisticated barrier defense system that includes both innate and adaptive immune systems. However, infants who are born preterm do not have the benefit of an adequate immune response and, therefore, are more susceptible to bacterial injury, inflammation, and intestinal diseases such as necrotizing enterocolitis. In this review, we discuss the components of innate immunity that help to protect the small intestine as well as current knowledge about the role of these components in the pathophysiology of necrotizing enterocolitis.