Free radical production occurs continuously in all cells as a by-product of cell metabolism. In tandem, the human body has developed endogenous antioxidant systems as well as taken advantage of dietary exogenous antioxidants to process and detoxify free radicals appropriately. However, certain conditions may increase free radical production beyond the body's endogenous and exogenous antioxidant systems. The neonatal period is a vulnerable time for free radical damage and injury, particularly for preterm infants whose antioxidant defense systems have not fully matured. Endogenous and passively acquired exogenous antioxidant defense systems do not accelerate in maturation until late in the third trimester. To explore the complexities of these concepts, this article includes a description, an evolutionary perspective of oxygen, and a basic background on free radical chemistry in biology. In addition, this chemistry is applied to the etiology of many of the most common diseases seen in the neonatal period. Finally, the current research addressing clinical strategies in this area is critically appraised. Implications for practice and directions for further research are presented with an emphasis on strategies that support the prudent use of oxygen therapies.