Cutaneous, acral and mucosal subtypes of melanoma are being evaluated by whole-genome sequencing of 500 tumours from Australian patients. Analysis of the first 183 tumours (doi: 10.1038/nature22071) revealed a heavily mutated landscape of coding and non-coding mutations in cutaneous melanoma, displaying signatures of known and novel ultraviolet radiation mutagenesis. In marked contrast, acral and mucosal melanomas were dominated by structural changes and mutation signatures of unknown aetiology, not previously identified in melanoma. Expansion of the mucosal cohort, now including WGS data from Chinese cases, has identified novel driver mutations for this subtype and confirmed non-UV-driven aetiology. Analysis of genomes prior to treatment with immune checkpoint inhibitors is revealing strong relationships between drug response and mutation profile and histological subtype.