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Malignancy is the second most common single cause of death observed in organ transplant recipients. The excess cancer risk is related to intensity and duration of immunosuppressive therapy and inversely to recipient age. Immunodeficiency and (chronic/oncogenic) viral infections together constitute a major risk. Nonmelanoma skin cancer, Kaposi sarcoma, and posttransplant lymphoproliferative disease have standardized incidence ratios exceeding 10- or 50-fold. The mammalian target of rapamycin (mTOR) inhibitors, sirolimus and everolimus, are increasingly used after organ transplantation with potential advantages in virus-associated posttransplant malignancies as well as anti-cancer properties. Despite a seemingly clear mechanism of action and solid rationale for their use in cancer therapy, mTORis have met only modest success rates in clinical trials with advanced malignancies except for specific tumors, such as Kaposi sarcoma and mantle cell lymphoma. Because mTORis are primarily cytostatic, not cytotoxic, the observed clinical efficacy is a reflection of disease stabilization rather than tumor regression. Nonmelanoma skin cancers, in particular cutaneous squamous cell carcinoma, have the highest standardized incidence ratios in transplant recipients. Recent meta-analyses and randomized trials on secondary prevention of squamous cell carcinoma observed a reduction in cumulative tumor load, suggesting most benefit to be gained by early conversion to an mTOR inhibitor–based maintenance regime. There is ongoing debate on the mechanisms involved including withdrawal of the carcinogenic effects of calcineurin inhibitors and/or their impact on chronic (oncogenic) viral infections. At present, there is, however, insufficient evidence for the primary use of mTORis as protective agents against most other cancer types.