The use of oxygen in the treatment of neonates with respiratory distress has been reported for more than a century. Oxygen therapy is generally titrated to one or more measures of blood oxygenation and administered to reverse or prevent hypoxia. Individual responses to oxygen therapy vary greatly, depending on the particular cause of hypoxia and the degree of impairment. Despite this focused purpose, oxygen administration in this patient population has become complex. The longer we deliver this drug, the more we discover its beneficial and detrimental effects. New and innovative ways to deliver and monitor this therapy have improved outcomes. Despite this vast experience there still remain some unanswered questions regarding the use of oxygen in the neonatal environment. Nonetheless, oxygen is a major staple in our treatment arsenal for neonates.