Improvements in peri- and postoperative surgical techniques have greatly improved outcomes for pediatric patients undergoing cardiopulmonary bypass (CPB) in the treatment of congenital heart defects (CHDs). With decreased mortality rates, the incidence of adverse neurological outcomes, comprising cognitive and speech impairments, motor deficits, and behavioral abnormalities, has increased in those patients surviving bypass. A number of mechanisms, including ischemia, reperfusion injury, hypothermia, inflammation, and hemodilution, contribute to brain insult, which is further confounded by unique challenges presented in the pediatric population. However, a number of brain monitoring and preventative techniques have been developed or are being currently evaluated in the practice of pediatric CPB. Monitoring techniques include electroencephalography, near-infrared as well as visible light spectroscopy, transcranial Doppler ultrasound, and emboli detection and classification quantitation. Preventative measures include hypothermic perfusion techniques such as deep hypothermic circulatory arrest, low-flow CPB, blood gas management, and pharmacologic prophylaxes, among others. The present review summarizes the principles of brain insult, neurodevelopmental abnormalities, monitoring techniques, methods of prevention, as well as preexisting morbidities and risk factors in pediatric CPB, with a focus on brain protection. Clinical and translational research is presented with the aim of determining methods that may optimize neurological outcomes post CPB and guiding further study.