The development of systems that allow cardiopulmonary bypass have been responsible for the growth of our specialty. In recent years continuing reduction in the mortality associated with cardiac operations has reinforced our confidence in the reliability and safety of perfusion equipment. Cardiac surgeons are aware that the mortality for most cardiac surgical procedures has decreased dramatically and overall morbidity has been reduced significantly. However, it is still clear that cardiopulmonary bypass techniques are not perfect. Indeed, it is fair to say that the period of bypass still contributes to significant morbidity in most patients. In particular, cerebral injury, the focus of this review, is a significant problem for patients and their caregivers and for funding of health-care systems. Incidence rates for stroke are around 2% to 3%, with increased risk in elderly patients and other high-risk groups. This relatively low incidence of what is universally recognized as a serious complication may be contrasted with the much higher reported incidence of cognitive defects assessed by neuropsychologic testing. The incidence of cognitive defects is as high as 60% at 8 days postoperative with reduction to 25% to 30% incidence at 8 weeks and 12 months. There are a variety of ways, at least potentially, in which the brain may be injured during an operation with cardiopulmonary bypass, including reduced cerebral blood flow, microembolism and macroembolism, and a systemic inflammatory response. These mechanisms interrelate and produce synergistic, cumulative effects on brain function during and after the operation. Reducing the incidence and effects of this altered brain function will rely on both preventive and therapeutic strategies. These, in turn, must be based on an understanding of the pathophysiology of these mechanisms of cerebral injury and directed toward ways to optimize cerebral perfusion, minimize embolic vascular occlusion, and develop pharmacologic approaches to modify the systemic inflammatory response.