This chapter explores the complex physiologic changes and the multifaceted inflammatory response induced by cardiopulmonary bypass (CPB) in cardiac surgery. CPB, a critical component in many cardiac procedures, significantly alters normal physiology, invoking both humoral and cellular inflammatory responses. The chapter begins by detailing how CPB triggers the humoral inflammatory response, leading to a cascade of events that activate complement, coagulation, and fibrinolytic pathways. It then examines the cellular inflammatory and immune response, focusing on the roles of leukocytes and endothelial cells, including their cytokine release, and the consequent impact on the body’s immune response during CPB. Further, the chapter discusses not only the beneficial effect of hypothermia commonly used in CPB to decrease metabolic demand and provide organ protection but also explores its potential to exacerbate inflammatory reactions. The chapter then provides a detailed discussion about temperature and pH management during CPB and deep hypothermic circulatory arrest (DHCA) to provide a comprehensive understanding of this critical aspect of CPB management. Additionally, the chapter briefly reviews the potential dysfunctions of organ systems associated with CPB. It equips the cardiac surgery and anesthesia teams with detailed insights into the physiological changes and the inflammatory responses triggered by CPB, enhancing their understanding and management skills.