Allograft vasculopathy remains the nemesis of long-term survival in heart transplantation. Possible modifying risk factors such as obesity, diabetes, and hypertension should continue to be pursued aggressively. All patients should receive statins. Clinical trials will provide the evidence needed to ascertain whether mammalian target of rapamycin inhibitors should be used in de novo cardiac transplant recipients to attenuate cardiac allograft vasculopathy (CAV). Intravascular ultrasound appears to play a key role in the diagnosis and evaluation of new treatments, and may indeed represent a surrogate marker that can be used to tailor management and improve outcomes. A better understanding of CAV is needed to develop targeted preventive therapies. Ongoing research in native atherosclerosis and vascular biology may provide answers within the next decade.