Weaning from cardiopulmonary bypass (CPB) is a critical step in surgeries that require extracorporeal support. This transition begins after the procedure is completed and when the patient can support their own circulation and gas exchange function without CPB. In many hospitals, a structured checklist guides this transition. Clear and closed-loop communication among the interdisciplinary team, including anesthesiologists, perfusionists, surgeons, and operating room nurses, is essential during this sensitive phase to ensure patient safety. The team must proactively identify potential post-weaning challenges and develop a detailed plan tailored to the individual patient and procedure. TEE has become an essential tool for weaning from CPB, providing insights into the completeness of surgery and guiding specific interventions. A significant number of cardiac surgery patients experience difficulties during weaning from CPB, often attributed to structural or functional cardiac issues, prolonged CPB, vasoplegic syndrome, inadequate myocardial protection during CPB, or preexisting ventricular dysfunction. Anticipating these challenges and making prompt therapeutic decisions is essential for achieving a successful separation from CPB. This chapter will explore these complexities, providing a comprehensive overview of the weaning process, its challenges, and best practices to ensure optimal patient outcomes following procedures that utilize cardiopulmonary bypass.