Extracorporeal membrane oxygenation (ECMO) therapy has significantly improved outcome in the newborn, pediatric, and adult patient in respiratory and cardiac failure. Despite this therapy providing a life-saving technology, the morbidity in patients treated with ECMO therapy is primarily related to neurologic alterations and not pulmonary findings. For ECMO, this is not unexpected since most patients are being placed on ECMO support because of severe hypoxemia, with ECMO being considered a rescue therapy for respiratory failure in most instances. As use of ECMO becomes common place for infants and children in respiratory failure, our investigations into the outcome of these children must focus not only on survival versus nonsurvival, but on the causes of morbidity in this population. A further understanding of factors associated with morbidity may allow us to alter techniques used in extracorporeal life support (ECLS), hopefully to improve our long-term outcome in this population, while allowing us to expand use of these technologies to other populations such as the premature infant. This article will focus on the effect of ECMO on the brain, with the following chapter by Dr. Richard Jonas outlining the effect of cardiopulmonary bypass on the brain.