Long-term outcomes in renal transplantation have improved over the years but are still a matter of concern. Because patients typically require lifelong immunosuppression, the risks of cancer and infection associated with immunosuppressive agents continue to demand attention. Physicians strive endlessly to find the right balance between the level of immunosuppression required to prevent rejection and the level that will minimize dose-dependent side effects. Data presented in this paper suggest that some renal transplant recipients might have more than necessary immunosuppression during maintenance therapy and that reducing the immunosuppressant dose can decrease cancer incidence, without worsening long-term patient or allograft survival. Additionally, data were examined suggesting that immunosuppressive agents might be associated with different risks for cancer, specifically, the potential advantage of reduced cancer risk for sirolimus and sirolimus derivatives in comparison with standard immunosuppressive agents. Although promising, these preliminary results are from preclinical studies, and further study is warranted.