In 2011, the American Academy of Pediatrics (AAP) published a technical report on the lifelong effects of early toxic stress on human development, and included a new framework for promoting pediatric health: the Ecobiodevelopmental Framework for Early Childhood Policies and Programs. We believe that hospitalization is a specific form of toxic stress for the neonatal patient, and that toxic stress must be addressed by the nursing profession in order to substantially improve outcomes for the critically-ill neonate. Approximately 4% of normal birthweight newborns and 85% of low birthweight newborns are hospitalized each year in the highly technological Neonatal Intensive Unit (NICU). Neonates are exposed to roughly 70 stressful procedures a day during hospitalization, which can permanently and negatively alter the infant’s developing brain. Neurologic deficits can be partly attributed to the frequent, toxic, and cumulative exposure to stressors during NICU hospitalization. However, the AAP Report does not provide specific action steps necessary to address toxic stress in the NICU and realize the new vision for pediatric healthcare outlined therein. Therefore, this paper applies the concepts and vision laid out in the AAP Report to the care of the hospitalized neonate and provides action steps for true transformative change in neonatal intensive care. We review how the environment of the NICU is a significant source of toxic stress for hospitalized infants. We provide recommendations for caregiving practices that could significantly buffer the toxic stress experienced by hospitalized infants. We also identify areas of research inquiry that are needed to address gaps in nursing knowledge and to propel nursing science forward. Finally, we advocate for several public policies that are not fully addressed in the AAP Technical Report, but are vital to the health and development of all newborns.