As transplant medicine advances, new immunosuppressive regimens are increasing the long-term survival of solid organ transplant recipients (SOTRs). This growing population is at significantly increased risk for developing cutaneous malignancies, particularly squamous cell carcinoma (SCC), as a result of chronic immunosuppression. Conventional risk factors for the development of skin cancer, including fair skin type, advanced age, sun exposure, and genetic predisposition, also play a crucial role in the initiation and progression of SCC in SOTRs. Immunosuppressed patients develop more aggressive and more numerous SCCs than immunocompetent individuals, however. It is important to understand the mechanisms underlying immunosuppression-mediated SCC development to identify prognostic markers and to develop effective prevention and treatment strategies. This article addresses the fundamental differences between SCC in SOTRs and those in the general population, focusing on the role that immunosuppression plays in the pathogenesis of this malignancy.