The sequelae of rejection post-heart transplant (HTx) impact the quality of life as well as short- and long-term survival. The goal of optimal immunosuppression therapy after HTx is to achieve a state of immune quiescence, preventing rejection of the donor heart graft while minimizing immunosuppression complications. Despite advancements in the field of immunosuppression, a regimen that leads to prolonged survival and yet is void of associated morbidity, including infection, malignancy, and drug-related toxicities, has not been identified. Patients without elevated immunologic risk features may benefit from minimization of immunosuppression after HTx. In this chapter, we discuss various management approaches to minimize immunosuppression for HTx recipients, including prednisone weaning, calcineurin inhibitors (CNI) minimization, use of proliferation signal inhibitors (PSI) to reduce or replace CNI, tacrolimus monotherapy, in addition to leveraging novel assays (e.g., T cell immune function assay), artificial intelligence, and precision medicine to personalize immunosuppression therapy.