This chapter offers an in-depth exploration of the historical development and evolution of cardiopulmonary bypass (CPB), a pivotal advancement in modern medicine that enabled open-heart surgery and revolutionized cardiac care in the twentieth century. Despite its relatively recent inception, only about 70 years ago, CPB has undergone significant changes, shaping the practice of cardiac anesthesiology, surgery, and perfusion. We trace the origins of CPB back to its first successful clinical application by John H. Gibbon Jr. in 1953 and examine the collective efforts of numerous pioneers whose innovations laid the foundation for today’s advanced techniques. This narrative not only covers the key milestones and technological advancements but also reflects on the rapid progression of CPB, transforming it into the remarkably safe procedure it is known for today. Additionally, this chapter reviews the many changes and progress in CPB, addressing the often-overlooked recent history that has seen its practice evolve dramatically. It embarks on a captivating journey through the historical advancements and developments that have shaped modern CPB, including aortic cannulation techniques, arterial pumps, venous drainage systems, temperature and pH management, and the evolution of anticoagulation methods and ultrafiltration techniques. Additionally, the chapter explores the development of the perfusionist specialty, tracing its growth to the sophisticated practice it is today. The chapter aims to enlighten current practitioners about the rich history of CPB and inspire ongoing advancements in the field.