The field of heart transplantation was built upon the discoveries of immunity and tolerance by Landsteiner, Medawar, Burnet, and others, as well as technical advancements in surgical technique by Carrel. Since the first successful human heart transplant performed by Christiaan Barnard in 1967, there has been substantial progress in the field of heart transplantation, especially over the last several decades. With advances in immunosuppression and surgical techniques, the rates of acute rejection and infection leading to graft failure have declined. However, the detection of acute and chronic allograft rejection remains one of the most important yet unsettled matters. As such, many new horizons exist for further advancement of the field of heart transplantation and for improving the outcomes of the patients we serve.