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Mucosal melanoma is a rare and aggressive malignancy arising from anatomically distinct mucosal sites that share a common melanocytic origin but differ in their clinical presentation, biology, and management. Accumulating evidence indicates that the anatomic site of origin fundamentally shapes clinical presentation, immune and microbial microenvironments, molecular drivers, and therapeutic vulnerabilities. In this review, we integrate epidemiologic, clinical, genomic, immunologic, microbiome, and translational data to systematically compare mucosal melanomas arising from the sinonasal tract, oral cavity, anorectal region, and vulvovaginal tract. We highlight striking site-specific differences in patterns of presentation and metastasis, immune and microbiome composition, enrichment of actionable molecular alterations, and responses to therapies. We further discuss how current preclinical models often fail to account for this biologic diversity, limiting translational progress. Collectively, these data support viewing mucosal melanoma as a unified disease entity with clinically meaningful heterogeneity shaped by anatomic site of origin, with important implications for classification, clinical management, and trial design.