High mortality rate for metastatic melanoma is related to its resistant to the current methods of therapy. Melanogenesis is a metabolic pathway characteristic for normal and malignant melanocytes that can affect the behavior of melanoma cells or its surrounding environment. Human melanoma cells in which production of melanin pigment is dependent on tyrosine levels in medium were used for experiments. Peripheral blood mononuclear cells were derived from the buffy coats purchased from Life blood Biological Services. Cell pigmentation was evaluated macro- scopically, and tyrosinase activity was measured spectrophotometrically. Cell proliferation and viability were measured using lactate dehydrogenase release MIT. [3H]-thymidine incorporation and DNA content analyses, and gene expression was measured by real time RT-PCR. Pigmented melanoma cells were significantly less sensitive to cyclophosphamide and to killing action of IL-2- activated peripheral blood lymphocytes. The inhibition of melanogenesis by either blocking tyrosinase catalytic site or chelating copper ions sensitized melanoma cells towards cytotoxic action of cyclophosphamide, and amplified immunotoxic activities of IL-2 activated lymphocytes. Exogenous L-DOPA inhibited lymphocyte proliferation producing the cell cycle arrest in Gl/0 and dramatically inhibited the production of IL-lbeta, TNF-alpha, IL-6 and IL-10. Thus, the active melanogenesis could not only impair the cytotoxicaction of cyclophosphamid but also has potent immuno suppressive properties. This resistance to a ehemotherapeutic agent or immunotoxic activity of lymphocytes could be reverted by the action of tyrosinase inhibitors. Thus, the inhibition of melanogenesis might represent a valid therapeutic target for the management of advanced melanotic melanomas. ©2008 Wiley-Liss, Inc.