NEC has remained a devastating disease as the pathogenesis remains incompletely understood. Animal models using rodents and pigs have been instrumental to establish the necessary risk factors linked to NEC, namely prematurity of the host, enteral feeding, and microbial colonization. The major advantages of rodent models are low cost and the ability to test how genetic disruption of target genes influences NEC. In the past 10 years, the use of the pig has rapidly emerged as a major experimental model to study NEC. Important advantages of the piglet model are its viability after premature birth, the spontaneous development of NEC, the distinct similarity to the gastrointestinal physiology of the human preterm neonate, and the ability to use standard clinical support approaches such as TPN. Preterm pig studies have shown the protective effects of germ-free conditions, antibiotics, and fecal microbiome transfer providing strong evidence that the microbiome is a key contributing factor in NEC pathogenesis. Studies also suggest that preterm pigs fed breast milk derived from different species, including porcine, bovine, and humans, can protect against NEC, suggesting there are common functional properties of natural milks. In addition, pig studies have identified the protective effects of nutrients, including lactose and arginine, to reduce the incidence of NEC. Studies in preterm pigs have also demonstrated the utility of abdominal near-infrared spectroscopy to noninvasively identify risk and monitor progression of NEC.