In East Asian culture, lighter skin tone is more preferable among the female population. Moreover, irregular hyperpigmentations such as solar Lentigines, melasma, and freckles are of concern in both Asia and western countries. Due to the high demand and potential for skin whitening products, the search for safe and effective depigmenting agents has become a popular research area. Hypopigmentation agents, also known as skin-whitening agents, are widely used to lighten the skin tone or treat abnormal hyperpigmentation by inhibiting the melanogenesis process. Cudrania tricuspidata, a deciduous tree growing in East Asia, is rich in isoprenylated xanthones and flavonoids. According to the previous research from our laboratory, oxyresveratrol and trans-dihydromorin purified from the twigs of Cudrania tricuspidata, are potent mushroom tyrosinase inhibitors, and may effectively inhibit the melanogenesis process in melanocyte. In this study, two cell cultures are exploited: B16 cell and melan-a cell. B16 murine cell line is selected as it is widely used in current research for the search of melanogenesis inhibitors. However, as B16 cells are highly metastatic tumor cells, a normal epidermal cell-based system should also be considered. Thus, Melan-a cell line, a normal epidermal melanocyte is utilized. The hypopigmenting effects of oxyresveratrol and trans-dihydromorin in these two cell lines are evaluated by measuring the melanin content in SRB assay. Their mechanisms of action are also identified by examining the inhibitory effects on cellular tyrosinase activity, l-dopa oxidative activity, as well as the related gene mRNA expression and protein expression.