During the screening of herbs for inhibition of melanogenesis, it was observed that ethanolic extract of Angelicae Gigantis Radix (AGE) effectively inhibited isobutylmethylxanthine-induced melanogenesis in B16 melanoma cells. The melanin content was significantly decreased by AGE in a dose-dependent manner, and no cytotoxicity was observed at the effective concentrations. Decreased melanin content was accompanied by reduced enzyme activity as well as reduced expression of tyrosinase protein and mRNA. The level of tyrosinase-related protein 1 and 2 mRNAs was also decreased by AGE. Additionally, AGE effectively inhibited alpha-melanocyte stimulating hormone- and forskolin-induced melanogenesis, and downregulated the mRNA expression of microphthalmia-associated transcription factor, a master transcriptional regulator of melanogenic genes. These results suggest that AGE acts as a putative hypopigmenting agent through downregulation of tyrosinase expression induced via a cAMP-dependent pathway.