Chronic allograft nephropathy (CAN) is, besides death of the recipient with graft function, the most common cause of renal transplant loss. It is characterized by loss of function and replacement of tissue by fibrotic material. The pathogenesis is not clear, but seems to be multifactorial and involves events both early and late after transplantation. Alloantigen-dependent mechanisms seem to be crucial for the development of chronic rejection (CR). Although modern immunosuppressive drugs have reduced the number and severity of acute rejection episodes, their effects on CR are less obvious. In this review we discuss the role of direct and indirect antigen presentation in the development of CR, and we will focus on the production of antibodies directed against HLA and non-HLA antigens on the graft and their influence on CR.