Recent epidemiologic studies of the risk factors for early and late phases of transplant coronary artery disease (TxCAD) have identified metabolic abnormalities such as hyperlipidemia and insulin resistance as important risk factors, independent of rejection. In randomized trials, calcium channel blockers and hydroxymethylglutaryl coenzyme A (HMG-CoA) reductase inhibitors were shown to decrease coronary artery intimal thickening and stenosis. Furthermore, HMG-CoA reductase inhibitors significantly decreased allograft loss during the first year after transplantation, resulting in a survival benefit, independent of TxCAD and cholesterol lowering. Prevention of acute allograft failure is consistent with known immunomodulatory actions of HMG-CoA reductase inhibitors, and the effects of calcium blockers in preventing TxCAD might have an immunologic basis by virtue of alterations of cyclosporine pharmacodynamics. Hence these two strategies for targeting antigen-independent mechanisms should lead to a significant reduction in the incidence of TxCAD, a goal that has until this time defied all the advances in immunosuppression during the past three decades of heart transplantation.