The depigmenting effects of oxyresveratrol and trans-dihydromorin were investigated in b16F10 cell line and its synergetic melan-a cells, as well as in 3-dimensional skin models. But their inhibitory effects were different in two cell lines. In b16 cells, oxyresveratrol showed stronger depigmenting effect than trans-dihydromorin, with greater suppression on tyrosinase activity. Both of them induced post-transcriptional degradations of microphthalmia-associated transcription factor (MITF), leading to significant decreases of tyrosinase related protein 1 (TRP-1) and tyrosinase related protein 2 (TRP-2) production. In melan-a cells, trans-dihydromorin exhibited stronger inhibition on melanin synthesis. It also induced greater suppression on the levels of tyrosinase, TRP-1 and TRP-2 via MITF down-regulation at both transcription and translation level. Evaluations in artificial skin model also demonstrated the depigmenting effects of trans-dihydromorin. In conclusion, we found that trans-dihydromorin is an effective hypopigmenting agent in normal skin cells. Furthermore we demonstrated that hypopigmenting agents effective in melanoma system may not be effective on normal melanocytes, indicating that a non-tumor melanocyte system is more suitable for the screening of hypopigmenting agents.