Simple SummaryIn this review, we describe the recent studies that define the genetic alterations and composition of the stroma of oral and cutaneous squamous cell carcinomas (OSCC and CSCC, respectively). Mutations in tumor suppressor genes and protooncogenes cooperate in determining the differentiation, aggressiveness, and metastatic potential of these types of cancers. Driver mutations in tumor suppressor genes are more frequently observed in OSCC than CSCC. We also describe the differential composition of the tumor microenvironment and how this influences the aggressiveness of each tumor type. Although both OSCC and CSCC tumors are highly infiltrated by immune cells, high levels of tumor-infiltrating lymphocytes have been more frequently reported as predictors of good responses in OSCC than CSCC.AbstractSquamous cell carcinomas arise from stratified squamous epithelia. Here, a comparative analysis based on recent studies defining the genetic alterations and composition of the stroma of oral and cutaneous squamous cell carcinomas (OSCC and CSCC, respectively) was performed. Both carcinomas share some but not all histological and genetic features. This review was focused on how mutations in tumor suppressor genes and protooncogenes cooperate to determine the differentiation, aggressiveness, and metastatic potential of OSCC and CSCC. In fact, driver mutations in tumor suppressor genes are more frequently observed in OSCC than CSCC. These include mutations inTP53(encoding pP53 protein),CDKN2A(encoding cyclin dependent kinase inhibitor 2A),FAT1(encoding FAT atypical cadherin 1), andKMT2D(encoding lysine methyltransferase 2D), with the exception ofNOTCH(encoding Notch receptor 1), whose mutation frequency is lower in OSCC compared to CSCC. Finally, we describe the differential composition of the tumor microenvironment and how this influences the aggressiveness of each tumor type. Although both OSCC and CSCC tumors are highly infiltrated by immune cells, high levels of tumor-infiltrating lymphocytes (TILs) have been more frequently reported as predictors of better outcomes in OSCC than CSCC. In conclusion, OSCC and CSCC partially share genetic alterations and possess different causal factors triggering their development. The tumor microenvironment plays a key role determining the outcome of the disease.