Post-transplant malignancy morbidity and mortality are important limitations in kidney transplantation. The incidence of malignancy has been estimated at 20% after 10 years of chronic immunosuppression. The aetiology of post-transplant malignancy is multifactorial, with the increased risk for malignancy in transplant recipients correlating with overall exposure to immunosuppression. Strategies to understand and minimize the risk of developing malignancy in the transplant population are needed. Calcineurin inhibitors (CNIs) have been linked with post-transplant malignancies, while mammalian target of rapamycin (mTOR) inhibitors have shown antineoplastic activities. The dual efficacy of sirolimus as an immunosuppressive and antitumour agent has been demonstrated experimentally and clinically. Clinical studies have demonstrated a lower incidence of new malignancies after renal transplantation in recipients receiving immunosuppression with mTOR inhibitors compared with CNIs. Therapeutic protocols involving mTOR inhibitors may protect an allograft from immunological rejection, while at the same time addressing the problem of cancer in this high-risk population. Newer sirolimus analogues, such as temsirolimus, have become a focus in pure oncological research and are being evaluated for antineoplastic effects on a variety of malignancies in clinical trials.