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Summary: Melanomas are known to exhibit phenotypic plasticity. However, the role cellular plasticity plays in melanoma tumor progression and drug resistance is not fully understood. Here, we used reprogramming of melanocytes and melanoma cells to induced pluripotent stem cell (iPSCs) to investigate the relationship between cellular plasticity and melanoma progression and mitogen-activated protein kinase (MAPK) inhibitor resistance. We found that melanocyte reprogramming is prevented by the expression of oncogenic BRAF, and in melanoma cells harboring oncogenic BRAF and sensitive to MAPK inhibitors, reprogramming can be restored by inhibition of the activated oncogenic pathway. Our data also suggest that melanoma tumor progression acts as a barrier to reprogramming. Under conditions that promote melanocytic differentiation of fibroblast- and melanocyte-derived iPSCs, melanoma-derived iPSCs exhibited neural cell-like dysplasia and increased MAPK inhibitor resistance. These data suggest that iPSC-like reprogramming and drug resistance of differentiated cells can serve as a model to understand melanoma cell plasticity-dependent mechanisms in recurrence of aggressive drug-resistant melanoma. : Setaluri and colleagues show that plasticity of melanocytes for reprogramming to iPSCs is inhibited by BRAFV600E oncogene and inhibition of BRAFV600E facilitates reprogramming of drug-sensitive, but not -resistant, metastatic melanoma cells. Melanoma-derived iPSCs (miPSCs) show limited pluripotency and tendency to differentiate along mixed neural and melanocyte lineage, but not to melanocytes, both in vitro and in vivo. Furthermore, miPSC-differentiated cells display acquired drug resistance. Keywords: melanocytes, malignant transformation, BRAF oncogene, melanoma tumor progression, melanoma iPSC reprogramming, melanoma plasticity, melanocyte differentiation, neural-like dysplasia, MAPKi resistance