The early results of clinical transplantation have improved progressively during recent years. However, the rate of attrition of organ allografts has not changed over time, despite greater understanding of the immunobiology of rejection, improved immunosuppression, more sophisticated methods of tissue typing and organ preservation, and better surgical and perioperative management. Chronic rejection is responsible for most late graft loss regardless of organ source (1). While the functional and morphological findings are well recognized, pathophysiological mechanisms remain obscure (2–4). Although many of the characteristic changes can be conceptualized as developing from antigen-driven host immunological activity, the influence of alloantigen-independent events is receiving increased attention. This review focuses on the role of both factors in the progression of chronic dysfunction of organ grafts.