A sizable number of cardiac surgical patients are difficult to wean off cardiopulmonary bypass (CPB) as a result of structural or functional cardiac abnormalities, vasoplegic syndrome, or ventricular dysfunction. In these cases, therapeutic decisions have to be taken quickly for successful separation from CPB. Various crisis management scenarios can be anticipated which emphasizes the importance of basic knowledge in applied cardiovascular physiology, knowledge of pathophysiology of the surgical lesions as well as leadership, and communication between multiple team members in a high-stakes environment. Since the mid-90s, transoesophageal echocardiography has provided an opportunity to assess the completeness of surgery, to identify abnormal circulatory conditions, and to guide specific medical and surgical interventions. However, because of the lack of evidence-based guidelines, there is a large variability regarding the use of cardiovascular drugs and mechanical circulatory support at the time of weaning from the CPB. This review presents key features for risk stratification and risk modulation as well as a standardized physiological approach to achieve successful weaning from CPB.