This chapter explores the critical aspects of assembling and setting up a cardiopulmonary bypass (CPB) circuit, emphasizing the hardware components and one-time-use disposables necessary for safe and effective operation. Starting with the historical context and evolution of the CPB machine, the chapter highlights the importance of understanding the fundamental principles and components of the machine. It provides detailed guidance on distinguishing between reusable hardware and disposable components, focusing on their roles and maintenance requirements. A step-by-step guide is offered for the preparation, assembly, and set-up of the CPB machine, including sterilization protocols, workspace organization, and the integration of safety devices. The priming process is covered in detail, addressing the selection of priming fluids, methods for air removal from the circuit, and adjustments based on patient-specific needs. Safety and quality control measures are emphasized, such as leak testing, connecting safety devices, and ensuring the functionality of monitoring systems. The chapter also covers the integration of advanced data capture technologies for real-time monitoring and postoperative analysis, contributing to improved patient outcomes and the development of best practices in cardiac surgery. With meticulous attention to detail and adherence to safety protocols, this chapter aims to equip perfusion students with the knowledge and skills necessary to effectively set up and manage a CPB circuit while providing the rest of the cardiac surgery team with a comprehensive understanding of CPB.