Cardiac allograft vasculopathy (CAV) is a form of coronary arterial stenosis and a leading cause of death in patients who survive beyond the first year after heart transplantation. Histopathologically, this lesion is concentric diffuse intimal hyperplasia of the arterial wall that is accompanied by extensive infiltration of inflammatory cells, including T cells. Many studies have explored the potential risk factors related to this arterial lesion and its pathogenesis. Continuous minor endothelial cell damage evokes inflammatory processes including T cell activation. Costimulatory molecules play crucial roles in this T cell activation. Many costimulatory pathways have been described, and some are involved in the pathogenesis of CAV, atherogenesis, and subsequent plaque formation. In this review, we summarize the present knowledge of the role of these pathways in CAV development and the possibility of manipulating these pathways as a means to treat heart allograft vascular disease and atherosclerosis.