Nitric oxide (NO) has critical roles in a wide variety of key biologic functions and has intricate transport mechanisms for delivery to key distal tissues under normal conditions. However, NO also plays important roles during disease processes, such as hypoxia-ischemia, asphyxia, neuro-inflammation, and retinopathy of prematurity. The effects of exogenous NO on the developing neonatal brain remain controversial. Inhaled NO (iNO) can be neuroprotective or toxic depending on a variety of factors, including cellular redox state, underlying disease processes, duration of treatment, and dose. This review identifies key gaps in knowledge that should prompt further investigation into the possible role of iNO as a therapeutic agent after injury to the brain. IMPACT: NO is a key signal mediator in the neonatal brain with neuroprotective and neurotoxic properties.iNO, a commonly used medication, has significant effects on the neonatal brain.Dosing, duration, and timing of administration of iNO can affect the developing brain.This review article summarizes the roles of NO in association with various disease processes that impact neonates, such as brain hypoxia-ischemia, asphyxia, retinopathy of prematurity, and neuroinflammation.The impact of this review is that it clearly describes gaps in knowledge, and makes the case for further, targeted studies in each of the identified areas.