The care of high-risk infants, both those born prematurely and those with medical, surgical, or developmental problems, has long been a major focus of nursing and healthcare. Care in the NICU focuses on meeting the physiologic, neurobehavioral, and developmental needs of these infants, with attention to the social interactive consequences of the NICU environment. This chapter focuses on the improved understanding of these factors and of the pathophysiologic problems encountered by infants in the NICU, along with the development of new management strategies, technologies, and caregiving approaches, have markedly improved the outcome of high-risk infants. Healthcare professionals need to be cognizant of the growing body of research regarding the impact of the NICU environment and family participation on neurodevelopmental outcomes. Role modeling, mentoring, coaching, and collaboration are essential in the promotion of optimal neuroprotective family-centered developmentally supportive care.