Post-transplant malignancy is recognised as being a major limitation to the success of solid organ transplantation and it is currently considered one of the unavoidable costs of long-term immunosuppressive therapy. However, the continual introduction of new immunosuppressive drugs and the growing knowledge about their different oncogenic profiles, requires a continuous evaluation of the available evidence on this topic. The incidence and risk of malignancy is elevated in solid organ transplant recipients compared with the general population. As proof of the relationship between immunosuppressive therapy and post-transplant malignancy, epidemiological data reveal that the length of exposure to immunosuppressive therapy and the intensity of therapy are clearly related to the post-transplant risk of malignancy, and that once cancer has developed, more intense immunosuppression can translate into more aggressive tumour progression in terms of accelerated growth and metastasis and lower patient survival. The association between malignancy and immunosuppressive therapy is mediated through several pathogenic factors. Indirectly, immunosuppressive drugs greatly increase the post-transplant risk of malignancy by impairing cancer surveillance and facilitating the action of oncogenic viruses. However, the direct pro- and anti-oncogenic actions of immunosuppressants also play an important role. The cancer-promoting effect of calcineurin inhibitors, independently of depressed immunosurveillance, has been demonstrated in recent years, and currently only mammalian target of rapamycin (mTOR) inhibitors have shown simultaneous immunosuppressive and antitumour properties. Reports of the initial results of the reduced incidence of cancer in organ transplant recipients receiving mTOR inhibitor therapy strongly indicate separate pathways for pharmacological immunosuppression and oncogenesis. The role of mTOR inhibitors has been firmly established for the treatment of post-transplant Kaposi's sarcoma and its role in the management of patients with other post-transplant malignancies should be clarified as soon as possible. Prevention of morbidity and mortality resulting from post-transplant malignancy should become a main endpoint in solid organ transplant programmes, and the choice and management of immunosuppressive therapy in each phase of transplantation plays a central role in this objective. Although comprehensive and rigorous information about the management of immunosuppressive therapy in transplant recipients at risk of or affected by cancer is still lacking, new experimental and clinical data about mTOR inhibitors offers novel approaches to this problem.