Supplemental oxygen plays a critical role in the management of infants born at the lower limit of viability, but not without the risk of complications resulting from high levels or prolonged exposure. Longitudinal studies of very premature infants, born at less than 28 weeks' gestation, establish a clear relationship between pulse oximetry saturation readings above 92%, or hyperoxia, and development of severe retinopathy of prematurity, chronic lung disease, and brain injury. Hyperoxia is neither natural nor random. It is an unintended consequence of intervention. A comprehensive review of the literature reveals a strong association between exposure to hyperoxia and subsequent expression of comorbidities. Owing to this knowledge, eradication of hyperoxia, and consequent reduction of sequelae, is a significant public health concern that deserves attention by the neonatal community. Although prospective, collaborative meta-analyses will soon provide needed additional data to inform practice, existing compelling evidence supports urgent practice change to reduce exposure to hyperoxia in very preterm infants.