Renal transplantation is now established as the therapy of choice for end-stage renal failure. The causes of renal allograft loss have changed with the introduction of new immunosuppressive agents. In the pioneer era of transplantation most renal allografts were lost during the first year after transplantation due to acute rejection episodes. Nowadays, chronic allograft nephropathy became the leading cause of graft loss. The causes of chronic allograft nephropathy can be divided into alloantigen-dependent and alloantigen-independent factors. Acute rejection episodes and histoincompatibility have a significant influence on late graft function. Although alloantigen-related injury is of major importance, alloantigen-independent factors also play a significant role in the progression of chronic allograft nephropathy. Prolonged ischemia time leads to induction of inflammation, resulting in fibrotic scarring or proliferation of mesenchymal cells. Donor related factors such as donor brain death, age, nephron number and gender have a definite impact on late allograft function. Posttransplant complications such as hypertension, metabolic factors and viral infections contribute to accelerated deterioration of the functional units of the kidney. Immunosuppressive agents such as cyclosporine and tacrolimus may cause vasoconstriction and decreased glomerular filtration rate. Moreover, non-compliance is one of the most important risk factor for chronic allograft loss. Regardless of the cause of the initial injury the pathophysiology of chronic allograft nephropathy seems to be the same. All these factors can induce endothelial injury, which leads to increased expression of cytokines and growth factors resulting in proliferative processes, remodelling and scarring of the graft. This paper reviews current knowledge about risk factors and their effect on long-term renal allograft function.