Although induction therapy has been used in heart transplantation for many years, its role has not been fully elucidated. Early safety concerns relating to OKT3 or intensive lymphocyte-depleting regimens have largely been addressed by modern induction protocols using rabbit antithymocyte globulin (rATG [Thymoglobuline® or ATG-Fresenius]) and interleukin-2 receptor antagonist (IL-2RA) agents, but although the number of randomized controlled studies has expanded there are still gaps in the evidence base. Rejection prophylaxis may be somewhat more effective with rATG than IL-2RA agents, but this has not been proven conclusively. Administration of induction therapy to support delayed introduction of calcineurin inhibitors in patients at risk of renal dysfunction is relatively well documented and widely used. Increasingly, it is recognized that sensitized patients and individuals with primary graft function are suitable candidates for induction therapy, and the possibility that rATG may inhibit cardiac allograft vasculopathy is also of considerable interest. Until the question of whether rATG is associated with increased risk of infection, routine prophylaxis is advisable. IL-2RA induction has an excellent safety profile. Dosing rATG according to lymphocyte count reduces cumulative dose without compromising efficacy. Further controlled trials are required to determine when and how to deploy induction most effectively following heart transplantation.