Despite improved immunosuppression and early allograft survival, long-term survival of allografts remains unchanged. Late renal allograft loss has traditionally been considered to result from repeated or unresolved episodes of acute rejection that lead to chronic immune-mediated allograft rejection. However, late renal allograft loss is known to occur in the absence of prior episodes of acute rejection. It is therefore proposed that factors other than histocompatibility influence long-term allograft survival. Evidence for nonimmunologic factors contributing to late allograft loss is presented. The central hypothesis is that following renal allograft mass reduction (from any etiology), glomerular hyperperfusion and hyperfiltration develop and lead to progressive renal dysfunction, proteinuria, histopathologic allograft changes, and late allograft failure. Multiple nonimmunologic factors that could contribute to reduced renal mass and ultimately promote chronic allograft loss as a result of hyperfiltration nephropathy are presented along with possible therapeutic strategies for the prevention and treatment of glomerular hyperfiltration.