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Small fragments of cell-free DNA that are shed by normal and tumor cells can be detected in the plasma of patients with advanced melanoma. Quantitative measurement of BRAF V600 mutant DNA within the cell-free DNA holds promise as a tumor-specific biomarker for diagnosis and therapeutic monitoring in patients with BRAF V600 mutant melanoma. Allele-specific quantitative PCR analysis for BRAF V600 E/E2/D/K/R/M mutations on DNA extracted from 1 ml of plasma is currently under evaluation in a number of ongoing prospective clinical studies. We report five patient cases that indicate the potential applications and utility of quantitative measurements of BRAF V600 mutant cell-free tumor DNA as a diagnostic test and as a therapeutic monitoring tool in stage IV melanoma patients treated with BRAF-targeted therapy or immunotherapy. Finally, we offer novel insights into the dynamics of cell-free tumor DNA in melanoma.