The receptor for hyaluronan (HA)-mediated motility (RHAMM) is a HA-binding protein located in the cytoskeleton and centrosome. RHAMM has multiple functions that manifest with different cellular localizations, for example, modulation of growth factor receptor, regulation of cell signaling pathways, and mitotic spindle assembly. In addition, its increased expression has major roles in tumorigenesis and can induce genomic instability and cancer progression. In head and neck cancers, increased expression of RHAMM is associated with high proliferation of cancer cells and decreased survival. CD44, a cell-adhesion molecule and HA receptor, can modulate intracellular signaling by forming complexes with RHAMM to promote invasion and metastasis of cancer cells. In this review, we provide an overview of the biological functions of RHAMM in non-neoplastic cells and cancer cells, as well as its association with CD44, and also introduce studies that particularly implicate RHAMM in the pathogenesis of head and neck cancers.