AMONG A VARIETY of nonimmunological parameters, donor nephron mass has been increasingly recognized as a predictive factor of renal graft outcome. Animal renal ablation studies reveal higher GFR and kidney weights in the low–nephron dose models, which are paralleled by higher degree of proteinuria and allograft glomerulosclerosis when compared with the higher nephron dose models. It is also demonstrated that the quantity of functioning renal mass is not only an independent determinant of chronic allograft nephropathy (CAN) but also a potent modulator of fundamental hemodynamic, cellular, and molecular processes, involving allograft macrophage infiltration and simultaneous upregulation of several growth factors and cytokines. Human kidney transplantation represents a good model of progressive renal mass ablation. Kidney allografts are susceptible to permanent losses of nephrons induced by several potential superimposed events along the graft lifeline. This may lead to glomerular hypertrophy and sclerosis, resulting in further reduction in nephron mass. This scenario has been proposed as an underlying mechanism for CAN. The baseline nephron supply in the graft, which is a random variable ranging from 4.10 to 8.10 nephrons, may be a major determinant of graft survival. Several antigen-independent factors have been shown to adversely affect the graft baseline nephron mass that may ultimately cause chronic graft dysfunction (CGD). These factors include the following: baseline graft histology donor type organ harvesting, donor age, gender, race, donor-recipient mismatches, organ senescence, and donor gene polymorphism. Kidneys from living donors, start with a far higher number of functional nephrons than cadaveric kidneys. This may explain their superior short-term and long-term graft survival when compared even with the most immunologically compatible cadaveric kidneys. Several peritransplantation factors associated with cadaveric donation, such as acute rejection, primary nonfunctioning graft, cold ischemia time exceeding 30 hours, cause of death other than trauma, black donors, and elderly donors, have been identified as potential risk factors for CGD. The effect of cadaveric heart beating donation (HBD) on baseline nephron mass is expected to be exaggerated in the non– heart beating (NHB) engrafted kidneys. The negative effect of old donor age on the graft survival is more evident even in the short term in cadaveric transplantation as compared to the living, reflecting the additive adverse effect of both ischemia and older age on the nephron mass. Augmenting nephron dose prevents proteinuria and glomerulosclerosis and preserves graft function in experimental models. Recipients of dual kidney transplants from marginal donors enjoy superior graft outcome to those receiving one single allograft despite having kidneys from older donors with poorer HLA matching. The progress in molecular genetic techniques is increasingly providing evidence for potential genetic predisposition for hypertension, renal diseases, increased rate of renal function loss, and renal allograft failure. This may explain the lower graft survival observed in kidneys engrafted in and from black donors. Graft outcome may be significantly improved by careful donor selection and handling. Younger donors when possible should be selected and older donors must preferably be matched with older recipients. Every attempt should be made to minimize ischemia time, particularly in older donors, through local use of both kidneys from older donors irrespective of the HLA matching and possibley engrafting both kidneys in the younger recipient to maximize nephron dose. Living donation should be encouraged. Graft damages may be minimized by improving harvesting techniques and preferably using HBD in cadaveric transplantation. The new longawaited nonnephrotoxic immunosuppressive or immunotolerant strategies should be widely adopted in organ transplantation. Angiotensin-converting enzyme inhibitors, and AT2 receptor antagonists should not only be used as firstline therapy for hypertension and proteinuria, but their introduction early in posttransplantation must become a routine.