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This review examines whether genomics clarifies the \u201cgray zone\u201d between benign and malignant pigmented lesions, or instead recasts existing histopathologic ambiguity in molecular terms, while also considering whether genomic classification shifts overdiagnosis upstream instead of resolving underlying diagnostic uncertainty. Across cytogenetic, mutation\u2010based, and gene\u2010expression platforms, current assays perform best in unequivocal melanoma\u2010versus\u2010nevus comparisons and lose accuracy in diagnostically ambiguous lesions where clarification is most needed. Gene expression profile (GEP) tests can be useful diagnostic aids in tissue\u2010rich equivocal lesions, including atypical Spitz tumors, MELTUMPs, and cellular blue nevus\/blue nevus\u2010like melanocytoma differentials. One clinicopathologic\u2010genomic model, the Merlin CP\u2010GEP test, has been prospectively validated for predicting sentinel lymph node status and is now recognized as supporting sentinel lymph node biopsy decisions in T1b\/T2a melanomas. Importantly, a low\u2010risk prognostic GEP class assignment should not displace the standard sentinel lymph node biopsy discussion. GEP tests are least useful for small, thin, equivocal junctional proliferations, precisely the lesions that are most difficult to diagnose. Pre\u2010biopsy non\u2010invasive assays carry the additional risk of lowering, rather than raising, the biopsy threshold. Overall, current genomic tools should be viewed as an adjunct to, rather than a replacement for, histopathology and clinical context.<\/jats:p>\n                  <jats:p>\n                    <jats:boxed-text content-type=\"graphic\" position=\"anchor\">\n                      <jats:graphic xmlns:xlink=\"http:\/\/www.w3.org\/1999\/xlink\" mimetype=\"image\/png\" position=\"anchor\" specific-use=\"enlarged-web-image\" xlink:href=\"graphic\/ijd70666-gra-0001-m.png\">\n                        <jats:alt-text>image<\/jats:alt-text>\n                      <\/jats:graphic>\n                    <\/jats:boxed-text>\n                  <\/jats:p>","DOI":"10.1111\/ijd.70666","type":"journal-article","created":{"date-parts":[[2026,9,29]],"date-time":"2026-09-29T14:35:10Z","timestamp":1790692510000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["Can We Diagnose Early Melanoma by Genomics?"],"prefix":"10.1111","volume":"65","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-2277-1549","authenticated-orcid":false,"given":"W. 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