Oxygen therapy has been one of the main challenges in neonatal intensive care units (NICU). The guidelines currently in use try to balance the burden of hypoxia and hyperoxia such as retinopathy of prematurity, bronchopulmonary dysplasia, and death. The goal of this paper is to review neonatal oxygenation and the impact of hyperoxia and hypoxia in neonatal outcomes as well as review the available literature concerning the use of Oxygen Reserve Index (ORiTM) in clinical practice and its potential in Neonatology, particularly in NICU. Pulse oximetry has been used to monitor oxygenation in newborns with the advantage of being a noninvasive and continuous parameter, however it has limitations in detecting hyperoxemic states due to the flattening of the hemoglobin dissociation curve. The ORiTM is a new parameter that has been used to detect moderate hyperoxia and, when used in addiction to spO2, could be helpful in both hypoxia and hyperoxia. Studies using this tool are mainly in the adult population, during anesthetic procedures with only a small number of studies being performed in pediatric context. Oxygen targets remain a major problem for neonatal population and regardless of the efforts made to establish a safe oxygenation range, a more individualized approach seems to be the more appropriate pathway. ORiTM monitoring could help defining how much oxygen is too much for each newborn. Despite its promising potential, ORiTM is still a recent technology that requires more studies to determine its true potential in clinical practice.