Cardiopulmonary bypass (CPB) is a complex biomechanical engineering undertaking and an essential component of cardiac surgery. However, similar to all complex bioengineering systems, CPB activities are prone to a variety of safety and biomechanical issues. In this narrative review article, the authors discuss the preventative and intraoperative management strategies for a number of intraoperative CPB emergencies, including cannulation complications (dissection, malposition, gas embolism), CPB equipment issues (heater-cooler failure, oxygenator issues, electrical failure, and tubing rupture), CPB circuit thrombosis, medication issues, awareness during CPB, and CPB issues during transcatheter aortic valve replacement.