Organ transplantation is the widely accepted treatment for end-stage organ failure. Since the first successful kidney transplant from an identical twin donor in 1954, researchers have been studying the effects of the immune system on transplantation outcomes. Although the surgery is technically successful, the majority of grafts from genetically disparate donors are rejected due to a number of factors that stimulate recipient immune responses, ultimately resulting in graft loss despite the chronic use of immunosuppressive (IS) drugs. Unfortunately, while short-term success has greatly improved with the development of novel IS drugs, the long-term graft survival of solid organs has not improved significantly over the last few decades. The problem of late graft loss is mainly attributed to development of chronic rejection. Therefore, understanding all of the immune mechanisms involved in transplant rejection is important to prevent graft dysfunction, and eventually, graft loss. In this review, we will give an overview of allograft rejection, the progression from acute to chronic rejection, and in addition, the recent discovery of a critical role for loss of self-tolerance and development of IL-17-dependent autoimmunity in chronic rejection.