Chronic rejection, the primary cause of late renal allograft loss, results from a complex interplay between immunological and non-immunological factors. During the past few decades, transplant research has focused almost exclusively on identifying more powerful and minimally toxic immunosuppressive strategies to prevent acute rejection and alloimmune response toward the graft, whereas poor attention has been paid to non-immunological factors. However, the discrepancy between remarkable improvements in the prevention of acute rejection and failure to ameliorate long-term graft outcomes suggests that non-immunological injuries may have an important role in the progressive loss of graft function. As kidney graft resembles the remnant kidney, in which a low nephron mass initiates a self-perpetuating process of progressive renal function loss, the same therapeutic tools able to retard progression of chronic renal disease are expected to be effective in kidney transplant patients as well. Indeed, high blood pressure (BP) levels, along with increased urinary protein excretion and hyperlipidemia, have been associated with reduced graft survival. Hence, strict BP control, renin–angiotensin system blockade to reduce proteinuria, and statins for hyperlipidemia control should probably represent the standard of care for kidney transplant patients. Furthermore, a multimodal nephroprotective strategy that includes smoking cessation, and tight glucose control for diabetes, might eventually be crucial to improve long-term graft outcomes.