The present study was designed to assess the potential inhibitory activity of curcumin on the alpha-melanocyte stimulating hormone (alpha-MSH)-stimulated melanogenesis signal pathway in B16F10 melanoma cells. The molecular mechanism of curcumin-induced inhibitory activity on the alpha-MSH-stimulated melanogenesis signal pathway, including expression of melanogenesis-related proteins and activation of melanogenesis-regulating proteins, was examined in B16F10 cells. Curcumin suppressed the cellular melanin contents and the tyrosinase activity in alpha-MSH-stimulated B16F10 cells. In addition, the expression of melanogenesis-related proteins such as microphthalmia-associated transcription factor (MITF), tyrosinase, and tyrosinase-related protein 1 and 2 was suppressed by curcumin in the alpha-MSH-stimulated B16F10 cells. Notably, a melanogenesis-regulating signal such as mitogen-activated protein kinase kinase (MEK)/extracellular signal-regulated kinase (ERK) or phosphatidylinositol 3-kinase (PI3K)/Akt was activated by curcumin in the B16F10 cells treated with or without alpha-MSH. The suppressive activity of curcumin on alpha-MSH-induced melanogenesis was down-regulated by PD98059 and by LY294002. Our results suggest that the suppressive activity of curcumin on alpha-MSH-stimulated melanogenesis may involve the down-regulation of MITF and its downstream signal pathway through the activation of MEK/ERK or PI3K/Akt.