In Brief Solid-organ transplant recipients are at increased risk of developing de novo malignancies compared with the general population, and malignancies become a major limitation in achieving optimal outcomes. The prevention and the management of posttransplant malignancies must be considered as a main goal in our transplant programs. For these patients, immunosuppression plays a major role in oncogenesis by both impairement of immunosurveillance, enhancement of chronic viral infection, and by direct prooncogenic effects. It is essential to manage the recipient with a long-term adapted screening program beginning before transplantation to use a prophylaxis to decrease infection-related cancer, to propose a viral monitoring, and to modulate the immunosuppression toward lower doses especially for calcineurin inhibitors. Indeed, strategies to induce tolerance or to allow a dramatic reduction of the immunosuppression burden are the more promising approaches for the reduction of the posttransplant malignancies. This review highlights the association between immunosuppression and chronic viral infections and malignancy, describing strategies to reduce the de novo cancer incidence after transplantation, from identification of high-risk patients to implementing immune monitoring tools, vaccination, anti-viral therapies, and immunosuppressive drug regimen changes.