This literature review examines perfusion safety in cardiothoracic surgery, with a primary focus on cardiopulmonary bypass (CPB) and circulatory devices. PRISMA guidelines were followed and various databases, including PubMed, MEDLINE, and Google Scholar, were searched using relevant keywords to identify pertinent studies and literature on the subject. The review traces the historical development of perfusion techniques and underscores the importance of equipment factors, personnel considerations, and perfusion management strategies in ensuring patient safety during CPB and circulatory device usage. Clinical aspects of perfusion safety, encompassing equipment safety features, temperature management, anticoagulation, and blood conservation, are discussed. Non-clinical aspects, including the implementation of standardized protocols, robust training structures, positive team dynamics, and the fostering of a safety-oriented culture, are also examined. Quality improvement initiatives for blood conservation, monitoring, and incident reporting are explored, along with an acknowledgment of the significant contributions of major perfusion societies and boards (AmSECT, SCPS, EBCP) in establishing standards and promoting excellence in the field. Challenges related to device design, patient selection, and perioperative management are addressed, highlighting the need for standardized practices and ongoing research to enhance perfusion safety. This comprehensive review underscores the enduring commitment to advancing perfusion safety and quality through systematic research, education, and collaborative efforts in cardiothoracic surgery.