Chronic, progressive, and irreversible loss of a transplanted kidney function, previously named chronic allograft nephropathy, is the leading cause of chronic allograft failure among kidney transplant recipients. Chronic allograft dysfunction (CAD) is a multifactorial process associated with progressive interstitial fibrosis and tubular atrophy. Current Data confirms that an additive series of time-dependent immunological factors such as acute and chronic antibody- and/or cell-mediated rejection and nonimmunological factors are involved in development of interstitial fibrosis and tubular atrophy as the fundamental parts of CAD. The use of calcineurin inhibitors has produced a major impact on achieving successful organ transplantation, however, although this assumption has been doubted recently, calcineurin inhibitors are deemed to be associated with nephrotoxicity and subsequent interstitial fibrosis, tubular atrophy, and kidney dysfunction. The early fibrotic changes are due to implantation stress, T-cell–mediated rejection, and infection, however, usually they do not lead to progressive fibrosis and allograft dysfunction per se. In the setting of CAD, many factors occurring lately after 1 year, such as chronic antibodymediated rejection, recurrent or de novo glomerulonephritis, and nonadherent adequately address the existence of ongoing injuries and progression to fibrosis. Identification of patients who are at risk, close clinical monitoring, and optimization and individualization of their maintenance immunosuppressive regimen are among the means that could help us to improve the long-term outcome of kidney transplantation.