Squamous cell carcinomas (SCCs) of the gingiva frequently invade the mandible or maxilla; this invasion is associated with a worse prognosis. The bone destruction associated with carcinomal invasion is mediated by osteoclasts rather than directly by the carcinoma. Therefore, if the cellular and molecular mechanisms by which oral SCC regulates bone invasion were known, it could inform the development of new therapeutic targets. Recently, dysregulation of the functional equilibrium in the receptor activator of NF-κB ligand (RANKL)/RANK/osteoprotegerin (OPG) triad has been shown to be responsible for osteolysis associated with the development of malignant tumors in bone sites. Furthermore, the administration of OPG or soluble RANK prevents bone metastasis by cancer cells. In this review, we discuss recent findings indicating that bone invasion by oral SCC is mediated via RANKL/RANK and may be successfully prevented by RANKL inhibition.