Immunotherapy studies in patients with melanoma have reported success in the expansion of tumour-specific effector T cells in vivo, but even in the presence of substantial numbers of functional T cells circulating in the blood, favourable clinical outcomes are scarce. This failure to induce robust clinical responses might be related to tumour-induced immune evasion, rendering the host tolerant to melanoma antigens. Immunosuppression in the tumour microenvironment mediated by regulatory T cells (Treg) is a dominant mechanism of tumour immune escape and is a major hurdle for tumour immunotherapy. Accumulation of Treg in melanoma is frequently recorded and the ratio of CD8-positive T cells versus Treg in the tumour microenvironment is predictive for survival of patients with melanoma. Hence, depletion of Treg seems to be a promising strategy for the enhancement of melanoma-specific immunity. Indeed, murine studies have shown that Treg depletion greatly increases the efficacy of immunotherapy. But despite the success of some strategies in depletion of Treg in patients, overall clinical efficacy has been disappointing. The lack of Treg specificity of the Treg depleting strategies applied so far imply that well-designed studies into dosage, timing, and administration regimens with more specific agents are urgently needed. Depletion of functional Treg from the tumour microenvironment as part of multifaceted immunotherapeutic treatments is a major challenge to induce clinically relevant immune responses against melanomas.