Critical events during cardiopulmonary bypass (CPB) can challenge the most experienced perfusionists, anesthesiologists, and surgeons and can potentially lead to devastating outcomes. Much of the challenge of troubleshooting these events requires a key understanding of these situations and a well-defined strategy for early recognition and treatment. Adverse situations may be anticipated prior to going on CPB. Atherosclerosis is pervasive, and a high plaque burden may have implications in surgical technique modification and planning of CPB. Hematologic abnormalities such as cold agglutinins, antithrombin III deficiency, and hemoglobin S have been discussed with emphasis on managing complications arising from their altered pathophysiology. Jehovah's witness patients require appropriate techniques for cell salvage to minimize blood loss. During initiation of CPB, devastating situations leading to acute hypoperfusion and multiorgan failure may be encountered in patients undergoing surgery for aortic dissection. Massive air emboli during CPB, though rare, necessitate an urgent diagnosis to detect the source and prompt management to contain catastrophic outcomes. Gaseous microemboli remain ubiquitous and continue to be a major concern for neurocognitive impairment despite our best efforts to improve techniques and refine the CPB circuit. During maintenance of CPB, adverse events reflect inability to provide optimal perfusion and can be ascribed to CPB machine malfunction or physiological aberrations. We also discuss critical events that can occur during perfusion and the need to monitor for organ perfusion in altered physiologic states emanating from hemodilution, hypothermia, and acid-base alterations.