The increased risk for the development of malignancies in transplant recipients is generally attributed to the debilitated immune system that results from chronic exposure to potent immunosuppressive drugs required to prevent graft rejection. While impaired immunity is clearly a key determinant, there is strong evidence that a constellation of other factors contribute to the pathogenesis of posttransplant cancers. In this article we discuss the underlying molecular and immunologic mechanisms that contribute to the development of de novo malignancies in transplant recipients, with particular focus on the two leading posttransplant neoplasia, skin cancer and Epstein-Barr virus (EBV)-associated posttransplant lymphoproliferative disorder (PTLD).