Perioperative risk of morbidity and mortality for neonates is significantly higher than that for older children and adults. At particular risk are neonates born prematurely, neonates with major or severe congenital heart disease, and neonates with pulmonary hypertension. Presently no consensus exists regarding the safest anesthetic regimen for neonates. Regional anesthesia appears to be safe, but does not reduce the overall risk of postoperative apnea. Former preterm infants require postoperative observation for apnea. The anesthesiologist caring for the neonate for major surgery should be knowledgeable of the unique physiology of the neonate and maintain the highest level of vigilance throughout.