Abstract: Melanomas are commonly found in the head and neck region, where 15% of cutaneous melanomas and approximately 50% of mucosal melanomas may occur. Recurrent or metastasized head and neck melanoma is resistant to standard treatments and thus a great challenge in oncology. Advances in the molecular pathogenesis of melanoma and in cancer immunology have led to the rational design and clinical implementation of various novel therapies for metastatic melanoma. For instance, BRAF and MEK inhibitors target the MAPK pathway, and these inhibitors exhibit high clinical response rates to BRAF-mutant melanoma. Specific therapies, including monoclonal antibodies that interfere with the pathways inhibiting T- cell functions, also modulate immune responses to melanoma; as such, these therapies have been applied to effectively treat melanoma.