The development of autoantibodies to different tissue-specific antigens in patients without existing history of autoimmune diseases suggests that autoimmunity may develop de novo after organ transplantation. In addition to allo-specific immune responses, tissue-specific autoimmunity also appears contribute to the host anti-graft response, and thus may affect long-term graft function. As graft failure caused by chronic rejection is a major challenge in clinical transplantation, understanding de novo autoreactivity after transplantation has important ramifications. This review investigates this emerging concept by discussing target antigens and possible pathways.