In conclusion, we believe that the information obtained from these studies described in this article will allow us to delineate UVR-induced HA (small vs. large HA)-mediated CD44 signaling mechanisms and subsequent keratinocyte activities, as well as to provide important HA-based and vitamin D-related therapeutic approach regarding the treatment of UVR-induced keratinocyte transformation and skin cancer progression. This evidence concerns the gene CD44 and skin neoplasm.