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Somatic mutation analysis of melanoma has been performed at the single gene level extensively over the past several decades. This has provided considerable insight into the critical pathways controlling melanoma initiation and progression. During the last 5 yr, next-generation sequencing (NGS) has enabled even more comprehensive mutational screening at the level of multigene panels, exomes and genomes. These studies have uncovered many new and unexpected players in melanoma development. The recent landmark study from The Cancer Genome Atlas (TCGA) consortium describing the genomic architecture of 333 cutaneous melanomas provides the largest and broadest analysis to date on the somatic aberrations underlying melanoma genesis. It thus seems timely to review the mutational landscape of melanoma and highlight the key genes and cellular pathways that appear to drive this cancer.