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Zachary A Vesoulis,1 Danielle P Sharp,2 Natasha Lalos,1 Devon P Swofford,1 Valerie Y Chock2 1Department of Pediatrics, Washington University, St. Louis, MO, USA; 2Department of Pediatrics, Stanford University, Palo Alto, CA, USACorrespondence: Zachary A Vesoulis, 660 S. Euclid Ave, Campus Box 8116, St. Louis, MO, 63110, USA, Tel +1 314-454-6148, Email vesoulis_z@wustl.eduAbstract: Conventional clinical practice in the neonatal intensive care unit (NICU) often fails to actively monitor the brain, relying on reactive strategies and imprecise risk indicators. The introduction of Near-Infrared Spectroscopy (NIRS) enhances current approaches to brain monitoring, offering non-invasive, real-time, continuous, and tissue-specific measures of oxygen saturation. NIRS leverages the physics of light to provide a comprehensive evaluation of oxygen delivery and consumption. This review covers the principles of NIRS, normative values for cerebral oximetry, and its applications in various clinical scenarios. Current clinical applications of NIRS span diverse areas, including intraventricular hemorrhage, white matter injury, anemia, congenital heart disease, and hypoxic-ischemic encephalopathy (HIE). NIRS demonstrates its potential in predicting and preventing adverse outcomes, particularly in optimizing cerebral oxygenation during cardiac surgery and guiding respiratory support in neonates. Key highlights of this review include the role of NIRS for the detection of cerebral hypoxia, even when other monitors do not show signs of clinical deterioration, a discussion of new methods for quantifying cerebral autoregulation and the connection to brain injury, and the potential utility NIRS monitoring offers for critically ill infants, such as those with congenital heart disease. The comprehensive insights provided by NIRS, if translated effectively into clinical practice, have the potential to improve the care and outcomes of neonates in the NICU.Keywords: NIRS, neonatal, brain injury, intraventricular hemorrhage, white matter injury, hypoxic ischemic encephalopathy, seizures, congenital heart disease