Merkel Cell Carcinoma (MCC) is an uncommon yet highly malignant form of skin cancer, frequently linked to the Merkel cell polyomavirus (MCPyV). This review comprehensively covers data from year 2000 to 2024, employing keywords such as MCC, MCPyV Oncoproteins, Immunohistochemistry, Southern Blot, Western Blot, Polymerase Chain Reaction (PCR), Digital Droplet PCR (ddPCR), Next-Generation Sequencing (NGS), and In Situ Hybridization (ISH). The search engines utilized were Google, PubMed Central, Scopus, and other journal databases like ScienceDirect. This review is essential for researchers and the broader medical community as it consolidates two decades of research on the genetic and molecular profiling of MCC, particularly focusing on MCPyV's role in its pathogenesis. It highlights the diagnostic advancements and therapeutic potential of targeting viral oncoproteins and provides insights into the development of both in vivo and in vitro models for better understanding MCC. The findings emphasize the significance of early detection, molecular diagnostics, and personalized treatment approaches, aiming to improve outcomes for patients with this malignant malignancy.