Necrotizing enterocolitis (NEC) is the most common gastrointestinal complication in human neonates, yet the pathogenesis of this disease remains poorly understood. A fundamental approach to understanding the etiology and underlying biology of NEC is the use of in vivo experimental animal models, primarly neonatal rodents and pigs. The rodent models using rats and mice have provided a much of the experimental evidence showing the protective influence of breast milk and the role of specific molecular mechanisms involved in the premature innate immune and intestinal injury response. A key advantage of mice is the abilty to test how genetic disruption of specific genes alters the NEC phenotype. More recently, pigs have emerged as an animal model of NEC and used to establish the role of bacterial colonization, prematurity, parenteral nutrition and antibiotic therapy. This review will outline some of the advantages and disadvantages of both rodent and pig models and highlight the lessons learned about NEC pathobiology from these different experimental models.