Vitamin A metabolism and signaling through nuclear retinoic acid receptors (RARs α,β,γ) regulate embryogenesis, immune functions, and cell differentiation in most cell types. RARγ is highly expressed in stratified squamous epithelial cells of the oral cavity and skin. While data indicate that RARγ agonism is anti-tumorigenic in oral cavity squamous cell carcinoma (OCSCC), the specific, primary gene targets of RARγ remain poorly characterized. Here, we define RARγ signaling pathways through integrating genome-wide RARγ binding by Cleavage under Targets and Release Using Nuclease (CUT&RUN), chromatin histone marks, and global transcriptomics ± agonists in human OCSCC cells and in human OCSCC cells with deletion of RARG (RARGKO).