Heart transplantation has become a well-established treatment option for patients with end-stage heart disease and currently has a one-year survival rate of 90%, a five-year survival rate of 70%, and 10-year survival rate of 50%. The introduction of anti-rejection treatment thirty years ago with drugs known as calcineurin inhibitors have resulted in a significant improvement in the survival of heart transplant recipients. However, most of this improvement occurs during the first year after transplantation. Beyond the first year, the mortality rate of heart transplant recipients has not changed, which indicates that the causes of late complications have not been affected in the last three decades by improvements in post-transplant care. It becomes apparent that in order to improve the late outcomes, the focus in heart transplant research needs to be shifted to the prevention and the treatment of late complications.