Although BRAF^V600E is well known to play an important role in the tumorigenesis of melanoma, its molecular mechanism, particularly the epigenetic aspect, has been incompletely understood. Here, we investigated the role of BRAF^V600E signaling in altering gene methylation in the genome of melanoma cells using a methylated CpG island amplification/CpG island microarray system and searched for genes coupled to the BRAF^V600Esignaling through methylation aberrations. The results indicated that a wide range of genes with broad functions were linked to BRAF^V600E signaling through their hyper- or hypomethylation. Expression of 59 genes hypermethylated upon BRAF knockdown was selectively tested and found to be largely correspondingly underexpressed, suggesting that these genes were naturally hypomethylated, and overexpressed with BRAF^V600E in melanoma. This BRAF^V600E-promoted hypomethylation was confirmed on genes selectively examined in primary melanoma tumors. Some of these genes were functionally tested and demonstrated to play a role in melanoma cell proliferation and invasion. As a mechanism of aberrant gene methylation driven by BRAF^V600E, expression of the DNA methyltransferase 1 and histone methyltransferase EZH2 was profoundly affected by BRAF^V600E. We have thus uncovered a previously unrecognized prominent epigenetic mechanism in the tumorigenesis of melanoma driven by BRAF^V600E. Many of the functionally important genes controlled by the BRAF^V600E signaling through aberrant methylation may prove to be novel therapeutic targets for melanoma.