Coronary artery disease in the transplanted heart, also known as cardiac allograft vasculopathy (CAV), is one of the major causes of mortality late after transplantation. It affects up to 50% of all heart transplant recipients within 5 years of surgery. The mechanisms of CAV are multifactorial and include both immune and nonimmune factors. Ischemia of the graft at the time of transplantation is one of the more important nonimmune factors, because this leads to endothelial cell injury. Immune factors involving cellular and humoral rejection can further insult the vascular endothelial cell, leading to a cascade of immunologic responses. The optimal treatment prophylaxis for CAV has not been established. The treatment approach to this major post-transplant complication includes modification of risk factors through medical therapies and strategies. The early use of diltiazem and/or pravastatin or simvastatin has been demonstrated to be effective in reducing the development of CAV, but does not completely prevent it. There are many ongoing studies involving newer immunosuppressive agents that may hold promise for the future.