To discover new molecules with an inhibitory activity of melanogenesis a hundred of scorpions, snakes, spiders and amphibians venoms were screened for their capacity to inhibit mushroom tyrosinase using 3,4-l-dihydroxyphenylalanine (l-DOPA) as substrate. The Argiope lobata spider venom proved to be the most active. HPLC fraction containing Argiotoxine-636 (ArgTX-636), a polyamine known for its numerous biological activities, was found to also show a good regulation activity of melanogenesis by inhibiting DOPA and 5,6-dihydroxyindole-2-carboxylic acid (DHICA) oxidases activities, wore by tyrosinase (TYR) and tyrosinase-related protein 1 (TRP-1), respectively. Our results demonstrate that ArgTX-636 reduced the mushroom tyrosinase activity in a dose-dependent way with a maximal half inhibitory concentration (IC) value of 8.34μM, when l-DOPA is used as substrate. The Lineweaver-Burk study showed that ArgTX-636 is a mixed type inhibitor of the diphenolase activity. Moreover, ArgTX-636 inhibits DHICA oxydase activity of mushroom tyrosinase activity with IC at 41.3μM. ArgTX-636 has no cytotoxicity in B16F10 melanoma cells at concentrations up to 42.1μM. The effect of ArgTX-636 on melanogenesis showed that melanin production in B16F10 melanoma cell decreased by approximatively 70% compared to untreated cells. ArgTX-636 displayed no significant effect on the TYR expression while the protein level of TRP-1 decreased in B16F10 cells. Thus, ArgTX-636 could have particular interest for cosmetic and/or pharmaceutical use in order to reduce important dermatoses in black and mixed skins.