Renal allograft failure is the most common cause of end-stage renal disease beyond the early posttransplantation period, accounting for 25% to 30% of patients awaiting renal transplantation. Despite recent advances in immunosuppressive therapy, improvements in long-term graft survival have not been commensurate with those observed in 1-year graft survival. The most common cause of chronic allograft loss is an incompletely understood clinicopathological entity sometimes called chronic rejection, chronic allograft dysfunction or in the case of kidneys, chronic allograft nephropathy. Although the precise mechanism(s) responsible for the characteristic pathological changes are still unclear, it is generally agreed that both alloantigen-dependent and alloantigen-independent factors influence the development of chronic allograft nephropathy. This article will address the potential mechanisms responsible for the pathogenesis of chronic dysfunction in solid organ grafts and the current approaches to management, including newer therapies designed to prevent the progression of the disease.