The pathophysiology of necrotizing enterocolitis (NEC) has not been clearly elucidated, but recent studies support the role of unbalanced pro-inflammatory signaling, leading to intestinal necrosis in premature infants. Although breast milk feeding is thought to reduce the risk of this condition, there are no preventive or therapeutic approaches that have consistently shown to be effective for this common and devastating disease. Recent studies show that probiotic colonization is abnormal in preterm neonates, and enteral supplementation with a variety of probiotic organisms can reduce the risk of disease. This chapter summarizes the current state-of-the-art regarding probiotics and NEC, but suggests caution until appropriately regulated products are available for use in this high-risk population.