Despite improvements in surgical techniques and the implementation of effective brain protection strategies, the incidence of brain injury after cardiac surgery has remained relatively constant over the years as patients have become older and sicker. Cognitive dysfunction is the most common clinical manifestation of brain injury after cardiac surgery. Its occurrence is related to a combination of three factors that are often associated with cardiopulmonary bypass (CPB): embolism, hypoperfusion, and the inflammatory response. However, such factors and their potential cerebral consequences are not exclusive to CPB. Postoperative cognitive dysfunction also afflicts patients who undergo cardiac surgery without CPB as well as nonsurgery patients who undergo transcatheter interventions. There is growing evidence that patient-related factors such as the presence of (cerebro)vascular risk factors play an important role in both early and late postoperative cognitive dysfunction.