The use of immunosuppression regimens containing a calcineurin inhibitor (CNI), an adjunct immunosuppressant (e.g., azathioprine, everolimus or mycophenolate mofetil) and corticosteroids has effectively reduced the risk of early graft loss due to acute rejection in heart transplant recipients. At present, late graft loss due to cardiac allograft vasculopathy (CAV) remains a major challenge for transplant teams. CAV is characterized by intimal hyperplasia as a result of endothelial cell injury. Factors relating to the transplant procedure itself (e.g., ischemic time and reperfusion injury), cardiovascular risks (e.g., donor age, hypertension, hyperlipidemia, pre-existing diabetes and new-onset diabetes after transplantation), immunologic risks (e.g., acute rejection episodes, anti-HLA antibodies) and the side effects of immunosuppression with CNIs or corticosteroids (e.g., cytomegalovirus infection, nephrotoxicity) have all been implicated in the development of CAV. The 2 main approaches to the prevention of CAV are modification of underlying risk factors (e.g., treatment with anti-hypertensive agents and lipid-lowering drugs, and optimizing the immunosuppressive regimen) and improvement in immunosuppression. CNIs remain the cornerstone of immunosuppressive regimens in heart transplantation, but new parameters for monitoring CNI exposure and new immunosuppressive regimens hold the promise of reduced overall CNI exposure with consequent reductions in vascular toxicity and improved clinical outcomes. Traditionally, trough levels of cyclosporine (C(0)) have been used to monitor exposure to cyclosporine and to assess the need for dose adjustment. However, optimal cyclosporine exposure can now be achieved through monitoring of cyclosporine levels 2 hours after dosing (C(2) monitoring). Furthermore, in a pivotal trial in heart transplantation, the new proliferation signal inhibitor, everolimus, plus full-dose cyclosporine and corticosteroids, has been shown to have improved impact on prevention of biopsy-proven acute rejection (and other efficacy end-points) and longer term on the prevention of CAV. In addition, there is evidence from studies in renal transplant recipients that everolimus plus reduced exposure cyclosporine is effective and well tolerated-with the regimen having a reduced potential for CNI-related nephrotoxicity and for other CNI-related cardiovascular side effects.