Chronic rejection following organ transplantation continues to be a major problem in the long-term survival of the engraftment. Recent literature points to role of both the humoral and cellular alloimmune responses in the pathogenesis of chronic rejection. Our recent studies have provided evidence for alloimmune-response-induced de novo development of immune responses to self-antigens in the post-transplant period in the pathogenesis of chronic rejection following lung, heart, and kidney transplantation. This review details our current understanding of two distinct yet inter-dependent immune processes in the immunopathogenesis of chronic rejection.