Metastatic melanoma is a poor prognosis skin cancer. Since conventional treatments including surgery and chemotherapy often fail, novel therapeutic strategies are needed. In particular, identification of melanoma associated antigen has fostered the progress of both active (vaccines) and adoptive immunotherapy. Some promising results have been obtained, but most melanoma patients are not yet cured possibly because of different immune-escape mechanisms operated by tumor cells. Several studies have addressed the use of interleukin (IL)-12 for melanoma therapy due to its immunoregulatory function and anti-tumor activity mediated by stimulation of T and NK effector cells. Unfortunately, IL-12 has shown considerable toxicity. We  have recently demonstrated that IL-12 exerts a direct anti-tumor activity on murine B16 melanoma cells expressing a functional IL-12 receptor (R). In our model low levels of endogenous IL-12 reduced proliferation, increased apoptosis, and defective microvessel formation of tumor cells. This review summarizes imformation about melanoma immunotherapy and highlights a novel mechanism of IL-12-mediated anti-tumor activity based upon the direct effect of the cytokine on IL-12R+ tumor cells. In this view, new therapeutic approaches may be planned including: i) pre-screening of melanoma patients for IL-12Rβ2 expression to identify potential responders, ii) administration of small and less frequent doses of IL-12 to avoid toxicity and iii) targeting of IL- 12 to IL-12R+ tumor cells, such as local administration in patients with skin tumors or injection of IL-12 fused to an antibody specific to tumor cells.