Despite major advances in cardiopulmonary bypass technology, surgical techniques, and anesthesia management, central nervous system complications remain a common problem after cardiopulmonary bypass. The etiology of neuropsychologic dysfunction after cardiopulmonary bypass remains unresolved and is probably multifactorial. Demographic predictors of cognitive decline include age and years of education; perioperative factors including number of cerebral emboli, temperature, mean arterial pressure, and jugular bulb oxygen saturation have varying predictive power. Recent data suggest a genetic predisposition for cognitive decline after cardiac surgery in patients possessing the apolipoprotein E epsilon-4 allele, known to be associated with late-onset and sporadic forms of Alzheimer's disease. Predicting patients at risk for cognitive decline allows the possibility of many important interventions. Predictive power and weapons to reduce cellular injury associated with neurologic insults lend hope of a future ability to markedly decrease the impact of cardiopulmonary bypass on short-term and long-term neurologic, cognitive, and quality-of-life outcomes.