With current immunosuppressive protocols, the incidence of graft loss to acute rejection has been markedly reduced; however, there has been no change in graft loss to chronic rejection. Recently, attention has been focused on the prevention and management of chronic rejection. Because neither the clinical course nor the biopsy is definitive for the diagnosis of chronic rejection, we believe both should be included in the definition. For kidney transplant recipients, the major risk factor for development of chronic rejection appears to be a previous acute rejection episode. Other risk factors include low‐dose maintenance immunosuppression and previous infection. For extrarenal transplant recipients, CMV and HLA mismatch have been implicated. Noncompliance probably plays a role for all patients. Laboratory studies have suggested that the development of chronic rejection (or lack thereof) may be due to an interplay of immunoregulatory factors. Patients with anti‐HLA antibodies have an increased incidence of late graft loss whereas those with antiidiotypic antibodies or with donor‐specific hyporesponsiveness (in MLC) have improved outcome and less chronic rejection. These findings have led to five testable hypotheses as to the pathogenesis of chronic rejection: I) chronic rejection is inadequately treated acute rejection; 2) chronic rejection can be prevented by maintaining adequate long‐term immunosuppression; 3) preventing or adequately treating infection will prevent chronic rejection; 4) the balance of immunoregulatory factors determines chronic rejection; 5) chronic rejection is the result of noncompliance. Each may play a role in some patients. Clinical and laboratory studies of risk factors and of the influence of intervention are necessary.