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Melanoma is the most aggressive form of skin cancer and advanced stages are inevitably resistant to conventional therapeutic agents. In particular, epigenetic strategies might open interesting new perspectives in combination with conventional ones. Current therapeutic strategies, in particular for metastatic melanoma, do not give great results in terms of survival. Herein, I review HDACis and microRNAs for melanoma. A critical discussion of all the recent findings on this topic is also included. In my view, further studies are needed to understand the toxicity of these treatments in order to improve survival of melanoma patients.