Late renal allograft loss is mainly the result of progressive histological damage. Both underimmunosuppression (rejection phenomena) and overimmunosuppression (calcineurin inhibitor nephrotoxicity) contribute to the progression of chronic histological damage. The current study was performed to elucidate the complementary impact of immune and nonimmune phenomena on renal allograft histology and function. By performing protocol biopsies, it was demonstrated that clinical and subclinical acute cellular rejection phenomena continue to play important roles, despite the use of the powerful combination of tacrolimus, mycophenolate mofetil, and steroids. Next to immune phenomena, the importance of nonimmune factors in renal allograft histological evolution was shown in protocol biopsy studies. Both in adult and in pediatric renal allograft recipients, the characteristics of the donor kidney (donor age, size discrepancy) appeared to be major determinants of the histological and functional evolution. This impact of donor characteristics was not only important in the immediate peritransplantation period, it was also shown that higher donor age increased the risk for progressive posttransplant histological injury and calcineurin inhibitor nephrotoxicity. Systemic levels of tacrolimus, if kept within a relatively narrow target window, were not associated with a risk for calcineurin inhibitor nephrotoxicity. However, we observed a significant association between renal allograft histology and P-glycoprotein (ABCB1) gene polymorphisms and expression, suggesting a role of this protein in the individual susceptibility to calcineurin inhibitor nephrotoxicity. Finally, the interplay between immune and nonimmune phenomena was demonstrated by the association between donor origin (deceased versus living) and local renal complement gene expression, by using whole-genome expression microarrays.