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Immunotherapies and targeted therapies have improved overall and progression\u2010free survival rates in metastatic melanoma patients. The effectiveness of these therapies decreases due to multidrug resistance (MDR). In contrast to previous reviews, this review extensively highlights the hallmarks of MDR and strategies for reversal of MDR. The review also critically evaluates the challenges in clinical translation of phytochemicals for metastatic melanoma and strategies to overcome these challenges. This review also highlights the various gaps that exist in metastatic melanoma (e.g., vascularized organ\u2010on\u2010a\u2010chip model has not been developed for melanoma which is largely influenced by angiogenesis). 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