In this study, we examined the effect of sesquiterpene lactones isolated from Calea urticifolia and Tanacetum parthenium (feverfew) on melanogenesis in mouse B16 melanoma cells. In response to 3-isobutyl-1-methylxanthin (IBMX), B16 melanoma cells underwent differentiation characterized by increased melanin biosynthesis. Treatment of sesquiterpene lactones at lower concentration (1 microM) significantly blocked IBMX-induced melanogenesis, but did not induce the inhibitory activity of cell growth. Among them, 2,3-epoxyjuanislamin exhibited a potent inhibitory effect on melanogenesis. Treatment of B16 cells with 2,3-epoxyjuanislamin elicited significant decreases in tyrosinase protein and mRNA levels. These results demonstrated that the inhibitory effects of sesquiterpene lactones on melanin biosynthesis may be due to the suppression of tyrosinase expression.