Swallowing is a critical function for survival and development in human neonates, and requires cross-system coordination between neurologic, airway, and digestive motility systems. Development of pharyngo-esophageal motility is influenced by intra- and extra-uterine development, pregnancy complications, and neonatal comorbidities. Primary role of these motility reflex mechanisms is to maintain aerodigestive homeostasis under basal and adaptive biologic conditions including oral feeding, gastroesophageal reflux, and sleep. Failure may result in feeding difficulties, airway compromise, dysphagia, aspiration syndromes, and chronic eating difficulties requiring prolonged tube feeding. We review the integration of cross-systems physiology to describe the basis for physiologic and pathophysiologic neonatal aerodigestive functions.