The field of genomic biomarkers in melanoma has evolved dramatically in the past few decades. Whereas much of the prior focus was on molecular assessment of tumor tissue, circulating tumor cells (CTCs), and cell-free circulating tumor DNA (ctDNA) as sources of a “liquid biopsy” in cancer patients provide promising potential as a method to assess tumor progression, identify targets for therapy, and evaluate clinical response to treatment. Blood biomarker assays have the advantage of being noninvasive, allow for dynamic evaluation of disease over a serial time frame, and help to address the issue of tissue sampling bias and tumor heterogeneity. However, there remains an assortment of technologies and techniques to isolate and detect CTCs and ctDNA and a standardized method has yet to be established. Despite these challenges, multiple studies have already demonstrated the clinical prognostic utility of blood-based genomic biomarker assays. With the advent of next-generation sequencing and genome-wide ctDNA analysis, this will undoubtedly lead to an improved understanding of tumor progression, help to identify new targets for treatment, and improve monitoring of treatment response and development of resistance.