Background: We compared the genomic alteration (GA) profiles of mCSCC, mPSCC and mSSCC to study impact on the targeted and immunotherapy options for the men and women suffering from these refractory cancers. Methods: 78 mPSCC, 604 mCSCC and 338 mSSCC underwent CGP using a hybrid-capture based assay. Tumor mutational burden (TMB) was determined on 1.1 Mbp of sequenced DNA and and microsatellite instability (MSI) was determined on 114 loci. Results: The HPV+/CDKN2A- status was significantly more frequent in the mCSCC than mPSCC or mSSCC (P < 0.0001). The GA/tumor frequencies were similar for mCSCC and mPSCC, but significantly higher in mSSCC (P < 0.0001). TP53 mutations were more common in mSSCC (UV light exposure) and mPSCC (likely due to loss of an original HPV+ status). TERT, NOTCH1 and FAT1 GA were more frequent in mPSCC and mSSCC whereas PIK3CA GA were more common in mCSCC. MTOR pathway targets (GA in STK11, FBXW7 and PTEN) were more common in mCSCC than mPSCC or mSSCC. MSI high status was extremely rare in all cases. TMB ≥ 10/20 mut/Mb frequencies were noteworthy in mPSCC and mCSCC but extraordinarily high in mSSCC. Examples of patients with mCSCC, mPSCC and mSSCC responding to targeted and immunotherapies will be presented. Conclusions: Although mCSCC, mPSCC and mSSCC share a variety of clinicopathologic features, the 3 tumor types can be sharply differentiated on CGP. The TP53, CDKN2A and HPV status of the tumor types differ significantly with HPV+ higher in the mCSCC group. There are opportunities for targeted therapies in all groups predominantly identified in the MTOR pathway. The relatively high numbers of cases with significantly elevated TMB in all 3 tumor types suggest that immunotherapies would be beneficial in a large subset of patients.