There is compelling evidence that MHC-driven immune processes play a dominant role in the development of cardiac allograft vasculopathy. Thus, it makes intuitive sense that tolerance, which eliminates donor alloreactivity, should protect against CAV. However, in the experimental literature, there are examples of CAV occurring in recipients rendered tolerant by either peripheral or central induction protocols. Why does transplant arteriopathy occur in recipients that have achieved a robust state of tolerance or in the animals devoid of T or B cell immunity? There may be immunological blindspots that persist even after a state of tolerance is achieved. These blindspots could contribute to the pathogenesis of chronic rejection (CR).