Purpose of review Increasingly, transplant clinicians are faced with providing candidates with increased risks for poorer outcome with donor grafts that also carry higher risks of failure. Understanding the role of immunosuppressive management in these combinations of higher risks remains important for optimizing results. Recent findings Few immunosuppressive protocols have been rigorously tested in the high-risk renal transplant setting. The two main risk categories accounted for in the trials are those ones that confer increased risks to renal function, usually carried by the donor organs, and those protocols defined by increased risk for immunological failure, mostly determined by recipient characteristics. The studied protocols generally involve reduction or avoidance of nephrotoxic drugs in the first case and use of lymphocyte-depleting agents in the case of increased immunological risk. In both scenarios, acceptable short-term results have been achieved. However, long-term results for high-risk transplants defined either by donor or recipient factors have yet to be reported. Summary The lack of long-term data for optimizing the right immunosuppressive regimen for a given donor/recipient risk profile remains an ongoing challenge for researchers and clinicians alike.