In this era of “personalized medicine,” much attention is being paid to different approaches that provide repeatable and safer insights into tumor evolution and heterogeneity. Since cutaneous melanoma is characterized by extreme heterogeneity and high tumor mutation burden (TMB) [144], the early detection of tumor-related changes such as chromosomal rearrangements, copy number variation, or mutations in oncogenes and tumor suppressor genes, is mandatory for the choice and adjustment of targeted therapy, treatment monitoring, and detection resistance [145]. In the last decade, the so-called “liquid biopsy” [146], which refers to a test of body fluids (i.e., blood, urine, and saliva), has emerged as a novel biomarker with significant application in translational research due to its ability to provide comparable (or more detailed) information than the conventional tissue biopsy [145]. Indeed, the analysis of circulating tumor cells (CTCs), cell-free circulating nucleic acids (cfDNA and cfRNA), and extracellular vesicles (EVs) via a minimally invasive blood draw has opened new avenues for cancer diagnostics, enhancing risk assessment, real-time monitoring of therapeutic efficacy, early detection of relapse, and monitoring of tumor evolution (Figure 3) [145,147,148,149]. Like all circulating tumor cells, Circulating Melanoma Cells (CMCs) are released into the bloodstream by the primary tumor and/or metastases [145,150]. Due to their high heterogeneity and rarity in the bloodstreams of metastatic melanoma patients [151,152], the continuous improvement of even more sensitive methods to detect and characterize them is of paramount importance. On the other hand, cell-free circulating DNA is produced from physiological functions such as apoptosis, necrosis, or secretion. Moreover, cancer patients have higher amounts of cfDNA than healthy controls [149,153]. Thus, the fraction of cfDNA that originates from tumor cells, called circulating tumor DNA (ctDNA), has been extensively studied as a putative disease marker, both in terms of quantity and composition. Indeed, the identification and monitoring of ctDNA using mutation-detection techniques (i.e., droplet digital PCR (ddPCR) and targeted next-generation sequencing (NGS) panels) has been well documented, and its potential as a promising biomarker for diagnosis, evaluation of treatment effectiveness, and as a tracker of tumor evolution has been well assessed in many cancers, including melanoma [149,154,155,156,157,158,159]. Finally, EVs actively participate in intercellular communication by taking part in the transfer of lipids, proteins, and RNA, thus suggesting a putative active role in cancer development [160,161]. Moreover, they have enormous potential as biomarkers, given that their tumor-derived cargo may be used for different applications, i.e., tumor burden estimation and survival prediction [145,162]. All things considered, the search for reliable biomarkers capable of tracking the disease evolution and heterogeneity in real-time may be successful in liquid biopsy, which is the sum of systemic disease. Since the use of targeted therapies and immunotherapy has significantly altered the natural history of melanoma, it is critical to closely monitor its genetic landscape to ensure its success. As previously stated, aberrant methylation of gene promoters can be a characteristic of cancer [163], and, as a result, the analysis of methylated DNA in liquid biopsy is an emerging field of interest [81,164,165]. It has already been demonstrated that hypermethylation of the promoters of certain selected genes can be used to distinguish melanoma patients from healthy individuals [81], demonstrating its utility as a diagnostic marker. Notably, DNA methylation patterns can change during melanoma progression; thus, longitudinal monitoring of DNA methylation in a non-invasive manner via liquid biopsy can provide real-time information about the behavior and stage of melanoma [80].