Heart transplantation has evolved into the treatment of choice for eligible patients with end-stage heart failure. Effective immunosuppression is critical to the success of this treatment, with the modern era beginning with the advent of cyclosporin A in the 1980s. In this Perspectives article, the major prospective, randomized trials of immunosuppression after heart transplantation are briefly reviewed. These trials provided the setting for the 2011 TICTAC trial, in which combined immunosuppression was compared with monotherapy. The results of the study are discussed, as are the implications of these data for future research, including the importance of frameworks, the risks and benefits of changes in immunosuppression regimen, the future of funding for such research, and the selection of appropriate end points in trials of heart transplantation. The presupposed need for multidrug immunosuppression is challenged, and the potential efficacy and benefits of monotherapy are explored.