Neurologic morbidity has been identified as increasingly problematic in neonates with congenital heart disease as surgical mortality rates have improved. The presence of "congenital brain disease" in patients with congenital heart disease represents a challenge in improving long-term neurologic outcomes. Mechanisms of central nervous system injury in infants undergoing cardiac surgery include hypoxia-ischemia, emboli, reactive oxygen species, and inflammatory microvasculopathy. Preoperatively, the primary focus is on preventing hypoxic-ischemic injury and thromboembolic insults. Modifiable intraoperative factors associated with central nervous system injury include, but are not limited to, pH management, hematocrit during cardiopulmonary bypass, regional cerebral perfusion, and the use of deep hypothermic circulatory arrest. Postoperatively, secondary neurologic injury may be related to post-cardiopulmonary bypass alterations in cerebral autoregulation and additional hypoxic-ischemic insult, seizures, or other issues associated with prolonged intensive care unit stay. In addition to prenatal and modifiable perioperative factors, genetic and environmental factors are known to be important. Unfortunately, modifiable perioperative factors may explain less of the variability in long-term outcomes than do patient-specific factors.