Using targeted sequence analysis and whole-exome sequencing (WES), we identify frequent mutation in both transforming growth factor-β (TGFβ) type 1 receptor (TGFBR1) and TGFβ type 2 receptor (TGFBR2) genes in human primary cutaneous squamous cell carcinoma (cSCC) samples. Here, TGFBR2 is linked to cutaneous squamous cell carcinoma.