The birth of cardiac transplantation can be traced back to the innovative French surgeon Alexis Carrel (Fig. 49-1) who performed the first heterotopic canine heart transplant with Charles Guthrie in 1905. [1 ] , [2 ] Twenty years later, the concept of cardiac allograft rejection was proposed by Frank Mann at the Mayo Clinic to explain the eventual failure of heterotopic canine allografts. [3 ] He described the rejection process as a “biologic incompatibility between donor and recipient” manifested by an impressive leukocytic infiltration of the rejecting myocardium. In 1946, Vladimir Demikhov of the Soviet Union successfully implanted the first intrathoracic heterotopic heart allograft. [4 ] He later demonstrated that heart-lung and isolated lung transplantation were also technically feasible. The use of moderate hypothermia, cardiopulmonary bypass, and an atrial “cuff” anastomotic technique permitted Norman Shumway and Richard Lower at Stanford University to surmount the formidable barriers of orthotopic heart transplantation using the canine model in 1960 (Fig. 49-2) . [5 ] The first human cardiac transplant was a chimpanzee xenograft performed at the University of Mississippi by James Hardy in 1964. [6 ] Although the procedure using Shumway's technique was technically satisfactory, the primate heart was unable to maintain the recipient's circulatory load and the patient succumbed several hours postoperatively. Despite great skepticism that cardiac transplantation would ever be successfully performed in humans, South African Christiaan Barnard surprised the world when he performed the first human-to-human heart transplant on December 3, 1967. [7 ] Over the next several years, poor early clinical results led to a moratorium on heart transplantation, with only the most dedicated centers continuing experimental and clinical work in the field. The pioneering efforts of Shumway and his colleagues at Stanford eventually paved the way for the re-emergence of cardiac transplantation in the late 1970s. The introduction of transvenous endomyocardial biopsy by Philip Caves in 1973 finally provided a reliable means for monitoring allograft rejection. [8 ] The advent of the immuno-suppressive agent cyclosporine dramatically increased patient survival and marked the beginning of the modern era of successful cardiac transplantation in 1981. [9 ] Heart transplantation is now a widely accepted therapeutic option for end-stage cardiac failure, with more than 2,700 procedures performed annually. [10 ]