Immunosuppression after heart transplantation has significantly reduced the incidence of cellular rejection and improved patient outcomes with the routine use of calcineurin inhibitors. Antimetabolites and proliferation signal inhibitors add to the improvement in patient outcomes, particularly with respect to the reduced burden of cardiac allograft vasculopathy. Patients with antibody sensitization are potentially at higher risk of postoperative complications. Sensitized patients are undergoing heart transplantation with increased frequency, in part due to the emergence of ventricular assist device use as a bridge to heart transplantation. Despite improvements in immunosuppressive therapies, many challenges face physicians and patients, which will further refine and improve care of the post-heart transplant patient.