Human chronic rejection is an uncommon feature of chronic allograft nephropathy, the major cause of late graft loss in kidney transplantation. Chronic rejection is a complex process, mediated, at least in part, by immunological mechanisms. T cells with donor, tissue or pathogen specificities that react with donor cells damage the graft tissue in synergy with antibodies. The cellular and humoral components of the immune system may be preformed or appear at both early and late time points following kidney transplantation. Both slowly contribute to the development of vasculopathy, glomerulopathy, tubular atrophy and tissue fibrosis, as observed in chronic rejection biopsies. Characterization of the blood transcriptome of patients prone to develop chronic rejection is an objective that may soon be achieved. However, despite increasing knowledge of the pathogenesis of late allograft failure and advances in the identification of patients at high risk, chronic rejection remains poorly responsive to immunosuppressive treatment, reinforcing the implication of both immune and nonimmune causes. Efforts aimed at diminishing the incidence of risk factors, such as acute rejection episodes, transplantation injury and human leukocyte antigen mismatching, and at controlling inflammation and scar processes, are thus important in chronic rejection prevention and control.