The worldwide incidence of malignant melanoma has been steadily increasing, and it has become a major public health problem in many countries. Melanoma has been considered as a prototypical “immunogenic” tumor on the basis of clinical observations showing that primary lesions can spontaneously regress and that immunosuppressed individuals have an increased incidence of melanoma. Thus, various immunological therapies have been intensively conducted for the treatment of melanoma. Interleukin(IL)-27 is a IL-12-related heterodimeric cytokine composed of p28 and EBV-induced gene 3 subunits that are structurally related to the p35 and p40 subunits of IL-12, respectively. Recent studies reveal that IL-27 exhibits not only potent antitumor immune activities via cytotoxic T lymphocytes or natural killer cells but also an antiangiogenic effect. We recently clarified that IL-27 possesses an antiproliferative activity on melanoma cells. This review summarizes antitumor responses induced by IL-27 and novel anti-melanoma activities of IL-27.