While advances in immunosuppression management have led to excellent 1-year survival after heart transplantation, long-term outcomes remain suboptimal. Contemporary therapies are associated with adverse sequalae, dominated by chronic kidney disease, and concomitantly by the inadequate control of humoral alloimmunity that is tightly linked to cardiac allograft vasculopathy. The dichotomy between the need for less toxicity and better control of humoral alloimmunity has driven a search for more effective regimens and for strategies to reverse humoral responses. This review provides an overview of immunosuppression in heart transplantation, beginning with critical historical context and followed by basic immunological principles underlying contemporary immunosuppression, the evolution of therapies over the past decade, and considerations for strategies to mitigate humoral alloimmunity. Perspective on the state-of-the field in the current era and considerations for future directions are also provided.