Cardiac allograft vasculopathy remains a major challenge to long-term survival after heart transplantation. Endothelial injury and dysfunction, as a result of multifactorial immunologic and nonimmunologic insults in the donor and the recipient, are prevalent early after transplant and may be precursors to overt cardiac allograft vasculopathy. Current strategies for managing cardiac allograft vasculopathy, however, rely on the identification and treatment of established disease. Improved understanding of mechanisms leading to endothelial dysfunction in heart transplant recipients may provide the foundation for the development of sensitive screening techniques and preventive therapies.