From the early days of transplantation onwards, increased cancer development in transplant recipients, who require immunosuppression to avoid graft rejection, has been recognized. Registry data indicate that approximately 10–30% of deaths are attributed to post-transplant malignancy, with an upward trend in this incidence as more patients have been exposed to chronic lifelong immunosuppression. In this Review, the overall incidence and most frequent types of cancer encountered are summarized, along with information about which transplant recipients are at the greatest risk of malignancy. Reasons for why differences exist in susceptibility to cancer in this patient population are examined, and approaches that might improve our understanding of the options available for reducing the incidence of this adverse effect of immunosuppression are described. Whether anti-rejection drugs have been successful in diminishing overall immunosuppressive burden, and consequently show any promise for decreasing post-transplant malignancies is also discussed. The topic shifts to one class of conventional anti-rejection drugs, the mammalian target of rapamycin (mTOR) inhibitors, which paradoxically have both immunosuppressive and anti-neoplastic properties. The complex activities of mTOR are reviewed in order to provide context for how these seemingly opposing effects are possible, and the latest clinical data on use of mTOR inhibitors in the clinic are discussed. The current and future perspectives on how best to normalize these unacceptably high rates of post-transplantation malignancies are highlighted.