SEPARATION from cardiopulmonary bypass (CPB) after cardiac surgery is a progressive transition from full mechanical circulatory and respiratory support to spontaneous mechanical activity of the lungs and heart. During the separation phase, measurements of cardiac performance with transesophageal echocardiography (TEE) provide the rationale behind the diagnostic and therapeutic decision-making process. In many cases, it is possible to predict a complex separation from CPB, such as when there is known preoperative left or right ventricular dysfunction, bleeding, hypovolemia, vasoplegia, pulmonary hypertension, or owing to technical complications related to the surgery. Prompt diagnosis and therapeutic decisions regarding mechanical or pharmacologic support have to be made within a few minutes. In fact, a complex separation from CPB if not adequately treated leads to a poor outcome in the vast majority of cases. Unfortunately, no specific criteria defining complex separation from CPB and no management guidelines for these patients currently exist. Taking into account the above considerations, the aim of the present review is to describe the most common scenarios associated with a complex CPB separation and to suggest strategies, pharmacologic agents, and para-corporeal mechanical devices that can be adopted to manage patients with complex separation from CPB. The routine management strategies of complex CPB separation of 17 large cardiac centers from 14 countries in 5 continents will also be described.