During the past 14 years, 746 hearts have been transplanted at the University of Pittsburgh. Immunosuppression has evolved from a CsA-based protocol with or without lympholytic prophylaxis to a tacrolimus-based protocol. Tacrolimus offers comparable survival to the conventional immunosuppression but is associated with lesser side effects and lower recurrent rejection. It also serves as an effective rescue agent for intractable rejection in patients receiving CsA-based immunosuppression. However, the shortage of donors, chronic rejection, and the morbidity associated with chronic use of nonspecific immunosuppression remain the major limitations in clinical transplantation. Currently, research at the University of Pittsburgh focuses on the induction of donor-specific transplantation tolerance in order to eliminate the morbidity associated with nonspecific immunosuppression and on left ventricular-assist devices as a bridge and/or an alternative to cardiac transplantation.