Many immunosuppressive drugs are associated with an increased risk of B-cell lymphoma, squamous cell carcinoma, and Kaposi sarcoma. Thirteen immunosuppressive drugs have been tested in 2-year carcinogenicity studies (abatacept; azathioprine; busulfan; cyclophosphamide; cyclosporine; dexamethasone; everolimus; leflunomide; methotrexate; mycophenolate mofetil; prednisone; sirolimus; and tacrolimus) and in additional models including neonatal and genetically modified mice; chemical, viral, ultraviolet, and ionizing radiation co-carcinogenesis, and in models with transplanted tumor cells. The purpose of this review is to outline the mechanisms by which immunosuppressive drugs can influence neoplasia, to summarize the available preclinical data on the 13 drugs, and to critically review the performance of the models. A combination of primary tumor and metastasis assays conducted with transplanted cells may provide the highest value for hazard identification and can be applied on a case-by-case basis. However, for both small molecules and therapeutic proteins, determining the relative risk to patients from preclinical data remains problematic. Classifying immunosuppressive drugs based on their mechanism of action and hazard identification from preclinical studies and a prospective pharmacovigilance program to monitor carcinogenic risk may be a feasible way to manage patient safety during the clinical development program and postmarketing.