Organ transplant recipients (OTRs) are at increased risk of developing non-melanoma skin cancers (NMSC). This has long been thought to be due to immunosuppression and viral infection. However, skin cancer risk among individuals with AIDS or iatrogenic immunodeficiency does not approach the levels seen in OTRs, suggesting other factors play a critical role in oncogenesis. In clinical trials of OTRs, switching from calcineurin inhibitors to mammalian Target of Rapamycin (mTOR) inhibitors consistently led to a significant reduction in the risk of developing new skin cancers. New evidence suggests calcineurin inhibitors interfere with p53 signaling and nucleotide excision repair. These two pathways are associated with NMSC, and squamous cell carcinoma (SCC) in particular. This finding may help explain the predominance of SCC over basal cell carcinoma in this population. mTOR inhibitors do not appear to impact these pathways. Immunosuppression, viral infection, and impaired DNA repair and p53 signaling all interact in OTRs to create a phenotype of extreme risk for NMSC.