Post-transplant malignancies, which occur either de novo or as cancer recurrences, are due to chronic exposure to immunosuppressive agents and are often more aggressive than those that develop in the non-transplant setting. Mammalian target of rapamycin (mTOR) inhibitors have antitumor and immunosuppressive effects. The dual effects of this class of agents may provide adequate immunosuppression to prevent organ rejection while simultaneously reducing the risk of post-transplant malignancy. mTOR inhibitors have become established approved agents for treating renal cell carcinoma and other cancers and, as reviewed herein, accumulating experience among organ transplant recipients collectively points toward a potential to prevent the development of de novo malignancies of various types in the post-transplant period. To date, most research efforts surrounding mTOR inhibitors and cancer control in the transplant population have been in the area of skin cancer prevention, but there have also been interesting observations regarding regression of post-transplant Kaposi's sarcoma and post-transplantation lymphoproliferative disorder that warrant further study.