Wnt/β-catenin signaling plays important roles in many developmental processes including neural crest-derived melanocyte development and migration. However, the effective contribution of Wnt/β-catenin pathway in melanogenesis in adult human melanocytes has not been fully elucidated. Here, we report that in melanoma cells and in normal human melanocytes, melanogenesis stimulation by α-melanocyte-stimulating hormone (α-MSH) induces phosphorylation of β-catenin-Ser675 and stabilization of β-catenin protein. Activation of protein kinase A by α-MSH attenuates glycogen synthase kinase-3β, which regulates ubiquitin-dependent degradation of β-catenin, suggesting a coordinated mechanism of β-catenin activity stimulation. Consistent with increased nuclear β-catenin, cyclic adenosine monophosphate (cAMP) elevation facilitates β-catenin-dependent transactivation of many Wnt target genes. Moreover, chromatin immunoprecipitation assays demonstrated an increased association of β-catenin with the proximal promoter of microphthalmia-associated transcription factor, the master regulator of pigmentation. These results demonstrate the existence of cross talk between the cAMP and Wnt pathways in melanocytes, suggesting that β-catenin could play a key role in the physiological regulation of epidermal melanogenesis.