The immunosuppressive medications used in organ transplant recipients (OTRs) to prevent allograft rejection are associated with an increased incidence of skin cancer in this population. Several classes of immunosuppressive agents exist, and the selection of which medication to use varies by organ type and with time. The tumorigenic potential and relative effects of different immunosuppressive medications on skin cancer risk have been studied. This article reviewed the history of the immunosuppressive agents and their mechanisms of action. A summary of the current literature on the relationship between skin cancer and the different immunosuppressives were included. Guidelines for management of OTRs in dermatologic practice were discussed.