MicroRNAs are known to be the important regulators of skin physiology and considered as new therapeutic targets to treat skin diseases. In this study, miR-125b was identified as a potent regulator of steady-state melanogenesis. We found that the expression of miR-125b was inversely related to pigment levels. A miR-125b mimic decreased the expression of pigmentation-related gene and melanin content, implying that miR-125b functions to decrease pigmentation. Moreover, we observed that the reduction in miR-125b expression in pigmented cells was at least partially due to the hypermethylation of the MIR125B-1 promoter, and miR-125b expression was regulated by intracellular cAMP levels.