Patients with melanoma are supposed to develop spontaneous immune responses against specific tumor antigens. However, several mechanisms contribute to the failure of tumor antigen-specific T cell responses, inducing immune escape. Importantly, immunosuppression mediated by regulatory T cells (Tregs) in tumor lesions is a dominant mechanism of tumor immune evasion. Based on this information, several therapies targeting Tregs such as cyclophosphamide, IL-2-based therapies, and antibodies against the surface molecular of Tregs have been developed. However, only some of these strategies showed clinical efficacy in patients with melanoma in spite of their success in shifting immune systems to antitumor responses in animal models. In the future, strategies specifically depleting local Tregs, inhibiting Treg migration to the tumor lesion, and Treg depletion in combination with other chemotherapies or immune modulation will hopefully bring benefits to melanoma patients.