Heart transplantation is a marvel of modern medicine for patients with end-stage heart failure. Decades of research and surgical innovation have overcome challenges in immunology, organ preservation, and patient care. From the earliest heart transplants on canines and primates, the field evolved through immunosuppressive therapies, development of the bioptome for endomyocardial biopsy and, recently, the use of cell free DNA and molecular microscopy for assessing rejection. Newer developments in organ preservation systems and transport systems bring remarkable increases in the availability of donors.