Neurologic complications after cardiac surgery are of growing importance for an aging surgical population. In this review, we provide a critical appraisal of the impact of current cardiopulmonary bypass (CPB) management strategies on neurologic complications. Other than the use of 20–40 μm arterial line filters and membrane oxygenators, newer modifications of the basic CPB apparatus or the use of specialized equipment or procedures (including hypothermia and “tight” glucose control) have unproven benefit on neurologic outcomes. Epiaortic ultrasound can be considered for ascending aorta manipulations to avoid atheroma, although available clinical trials assessing this maneuver are limited. Current approaches for managing flow, arterial blood pressure, and pH during CPB are supported by data from clinical investigations, but these studies included few elderly or high-risk patients and predated many other contemporary practices. Although there are promising data on the benefits of some drugs blocking excitatory amino acid signaling pathways and inflammation, there are currently no drugs that can be recommended for neuroprotection during CPB. Together, the reviewed data highlight the deficiencies of the current knowledge base that physicians are dependent on to guide patient care during CPB. Multicenter clinical trials assessing measures to reduce the frequency of neurologic complications are needed to develop evidence-based strategies to avoid increasing patient morbidity and mortality.