Cardiopulmonary bypass (CPB), a cornerstone of modern cardiac surgery, has seen remarkable advancements since its inception by John Gibbons Jr. Despite its significant evolution, CPB is still prone to unexpected crises. These catastrophic events, ranging from massive air embolism to mechanical failures, require swift recognition and management to prevent adverse outcomes. While playing a vital role in cardiac surgery by temporary replacing heart and lung function CPB still carries the potential for unforeseen crises that can potentially lead to dire patient outcomes. This chapter explores the complex and challenging CPB-related crises, carefully examining their causes, clinical manifestations, and management strategies. Addressing these CPB crises requires a collaborative, multidisciplinary approach, involving surgeons, anesthesiologists, perfusionists, and nursing teams. It highlights the essential principles of managing such crises, focusing on the importance of clear communication, rapid decision-making, and the application of standardized protocols.