Since the first heart transplantation (HT) in 1967, survival has steadily improved. Issues related to over- and under-immunosuppression are, however, still common following HT. Whereas under-immunosuppression may result in rejection, over-immunosuppression may render other medical problems, including infections, malignancies and chronic kidney disease (CKD). As such complications constitute major limiting factors for long-term survival following HT, identifying improved diagnostic and preventive methods has been the focus of many studies. Notably, research on antibody-mediated rejection (AMR) and cardiac allograft vasculopathy (CAV) has recently led to the development of nomenclatures that may aid in their diagnosis and treatment. Moreover, novel immunosuppressants (such as mammalian target of rapamycin [m-TOR] inhibitors) and strategies aimed at minimizing the use of calcineurin inhibitors (CNIs) and corticosteroids (CSs), have provided alternatives to the traditional combination maintenance immunosuppressive therapy of CSs, cyclosporine (CSA) or tacrolimus (TAC), and azathioprine (AZA) or mycophenolate mofetil (MMF). Research within this field of medicine is not only extensive, but also in constant progress. The purpose of the present review was therefore to summarize some major points regarding immunosuppressive therapies after HT and the balance between under- and over-immunosuppression. Transplant immunology, rejection, common medical problems related to over-immunosuppression, as well as induction and maintenance immunosuppressive drugs and therapies, are addressed.