The oropharyngeal administration of mother's milk—placing drops of milk onto the infant's oral mucosa—may serve as a preventative strategy against necrotizing enterocolitis (NEC) for extremely low-birth-weight (ELBW: birth weight <1000 g) infants. Necrotizing enterocolitis is a devastating gastrointestinal disorder which is associated with significant mortality for ELBW infants. Survivors are at risk for costly and handicapping morbidities, including severe neurological impairment. The oropharyngeal administration of mother's milk to ELBW infants may serve to expose the infant's oropharynx to protective (immune and trophic) biofactors (also present in amniotic fluid) and may protect the infant against NEC. Emerging evidence suggests that this intervention may have many benefits for extremely premature infants including protection against bacteremia, NEC, and ventilator-associated pneumonia, an earlier attainment of full enteral feeds, enhanced maturation of oral feeding skills, improved growth, and enhanced breast-feeding outcomes. While more research is needed to definitively establish safety and efficacy of this intervention, this article will examine biological plausibility and will describe the theoretical mechanisms of protection against NEC for ELBW infants who receive this intervention. Nurses play a key role in advancing the science and practice of this intervention. Future directions for research and implications for nursing practice will also be presented.