We examined mutations in BRAF exons 11 and 15 and N-RAS exons 2 and 3, in 77 metastatic melanoma cases and 11 melanoma cell lines. Significant differences in the mutation rates observed at different metastatic sites could not be detected. The most frequent mutation, the V599E amino acid substitution in BRAF exon 15, was observed in 31 of 77 (40%) tissues and 5 of 11 (45%) cell lines. Tandem base-pair substitutions encoding V599R and V599K amino acid changes were observed in two cases. Novel findings with respect to melanoma include a cell line possessing a 2 base-pair substitution in BRAF exon 11 and a case harboring mutations in both BRAF exon 11 and N-RAS exon 3. Our data show that BRAF mutation is common in melanoma metastases, regardless of their site, that mutations include both exons 11 and 15, and suggest that anti-RAS/RAF strategies may be effective in metastatic melanoma patients.