Melanoma is a malignancy with increasing incidence and a propensity to mimic other tumors and lose expression of characteristic markers. Here, we report a novel application for targeted next-generation sequencing of cancer gene panels, which enabled molecular correlation between a patient’s earlier melanoma and a rapidly progressive, undifferentiated form that quickly progressed to fatal disease. The patient, a 54-year-old man who recently received a diagnosis of a conventional melanoma with positive sentinel lymph node, presented 2 months later with acute renal failure, worsening respiratory function, and a large chest wall mass with peau d’orange findings suggestive of inflammatory carcinoma. A left chest wall punch biopsy showed a poorly differentiated epithelioid malignancy suggestive of disseminated carcinomatosis with extensive pan-cytokeratin expression and lack of expression of any melanocytic markers. Despite intensive treatment, the patient died 3 weeks later, with diffuse metastasis of unknown malignancy seen at autopsy. Next-generation sequencing performed on surgical samples of both the patient’s original melanoma and the undifferentiated left chest wall malignancy showed an identical, pathogenic BRAF V600E mutation, a finding deemed convincing evidence that the undifferentiated malignancy was a transformed, metastatic melanoma with a targetable molecular alteration. Prospectively, increasingly available next-generation sequencing–based assays may be of use to “trace the origin” of undifferentiated or anaplastic malignancies between metachronous, morphologically dissimilar samples based on shared mutation profiles. Such a strategy might prove helpful when several primary sites are considered and would complement traditional immunohistochemistry to assist in therapeutic planning even if targetable alterations are not identified.