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.