Approximately 50% of mucosal melanomas affect the head and neck region representing approximately 9% of all malignant head and neck tumors. The pathogenesis of this disease is unknown. Mucosal melanomas are characterized by an aggressive biological behavior, leading to a 5-year survival rate of less than 25%. Data for this review were identified by searches of Medline, Current Contents, PubMed, and references from relevant articles using the terms 'mucosal melanoma,' 'head and neck melanoma,' 'c-kit mutation in melanoma,' and 'c-kit inhibitors'. Therapy aims for the complete surgical excision of the primary tumor, whereas sentinel node biopsy is not established and present data do not support the addition of radiotherapy. Mutilating operations of larger tumors should be avoided, as they do not inhibit the frequent development of distant metastasis. C-kit mutations and amplifications are found in approximately 15-30% of mucosal and acral-lentiginous melanomas. Therefore, the use of so-called targeted therapies addressing molecular structures in mucosal melanomas seem to represent new promising treatment tools. In this study, we review the literature regarding epidemiology, molecular pathology, and therapy of mucosal melanomas of the head and neck emphasizing c-kit protein inhibiting treatment modalities for tumors carrying c-kit mutations.