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Oxygen is one of the most widely used drugs in the neonatal period. A lack of knowledge of oxygen metabolism and toxicity has prompted guidelines to fluctuate from liberal use to treat respiratory distress to restriction to avoid retinopathy of prematurity. In recent years, studies performed in the immediate postnatal period have revealed that newly born infants achieve a stable saturation only several minutes after birth. Moreover, the time needed to reach a saturation plateau is inversely proportional to a newborn's gestational age. As a consequence, guidelines have changed and recommend an individualized supplementation in the first minutes after birth with the inspiratory fraction of oxygen titrated against preductal pulse oximetry. However, randomized controlled trials have concluded that, after postnatal stabilization, keeping preterm babies within a low-saturation target range (85-89%) may lead to increased mortality while keeping them in a higher saturation range (91-95%) increases the risk of retinopathy of prematurity. The present state of the art in the management of oxygen supplementation recommends that caregivers in the delivery room allow preductal oxygen saturation to spontaneously increase in the first minutes of life; however, if supplemented, it should be titrated according to pulse oximeter readings and kept within the safe margins of the nomogram. Thereafter, if oxygen is still needed, it should be kept within stringent security margins (90-95%) to avoid deleterious consequences. Importantly, in babies with chronic lung disease, oxygen should be supplemented to allow the patient to grow and develop.