The success of cardiac transplantation has been largely attributable to the development of effective immunosuppressive regimens. The calcineurin inhibitors were pivotal in reducing the frequency of acute rejection and improving early survival. Newer agents, including mycophenolate mofetil and proliferation signal inhibitors, show some promise in further reducing episodes of acute allograft rejection and also having a significant impact on reducing transplant vasculopathy. The role of cytolytic induction therapy remains unclear, although its use may be most appropriate in the high risk presensitized transplant recipient. While the endomyocardial biopsy remains the gold standard for the diagnosis of acute allograft rejection, its invasive nature makes the test suboptimal. The presence of biopsy 'negative' rejection has also led to an appreciation for the role of antibody-mediated rejection in cardiac allograft dysfunction. Effective noninvasive evaluation of allograft rejection remains the ultimate challenge. While imaging technologies have some utility because of their ease of use, more sophisticated techniques such as gene-expession analysis from peripheral blood may show the greatest promise. Management of established acute allograft rejection has significantly improved with our understanding of the immune mechanisms involved. Therapies may be targeted specifically at cellular or humoral components of the immune system.