Melanoma is one of the most aggressive types of skin cancer with rapidly increasing incidence rate. The disease is largely considered incurable and the patients diagnosed with metastatic melanoma have a survival of not more than five years. Despite of the recent advances in anti-melanoma chemo- and immunotherapies, the available drugs are relatively toxic and responsive to only a limited subset of lesions. Currently, topical pharmacotherapy is demonstrated as an effective approach for the treatment of various skin cancers. Also, in vitro testing of melanoma cell lines and murine melanoma models has identified a number of relatively safe and effective phytochemicals. In this review, we described the use of topical pharmacotherapy for the treatment of skin cancers. Melanoma treatment by drugs targeting MAPK-pathway has also been discussed. Long non-coding RNAs and therapeutics targeting ER-associated pathways looks quite promising for the treatment of melanoma. Moreover, some natural anticancer compounds that have been reported to have anti-melanoma effects have also been described. At present a better understanding of genetics and epigenetics of initiation and progression of melanoma is needed for the identification of novel biomarkers and development of targeted therapeutics against melanoma.