Melanoma, a highly aggressive form of skin cancer, is characterized by rapid progression and high mortality. Recent advances in molecular pathogenesis have revealed genetic and epigenetic changes driving melanoma development. This review focuses on the molecular mechanisms in melanoma genesis, highlighting mutations in genes such as *BRAF*, *NRAS*, *c-KIT*, and *GNAQ/GNA11* that affect critical signaling pathways. The evolution of diagnostic techniques, including genomics, transcriptomics, liquid biopsies, and molecular biomarkers, has improved early detection and prognosis. Therapeutic advancements include targeted therapies and immunotherapies, which have transformed patient outcomes. The review discusses the efficacy, challenges, and prospects of these treatments, emphasizing the importance of personalized medicine and evidence-based therapy selection. Novel treatment strategies, such as neoantigen vaccines, adoptive cell transfer, microbiome interactions, and nanoparticle-based combination therapy, are explored, along with the potential of DNA damage response inhibitors. The integration of emerging therapies into clinical practice is crucial for overcoming resistance and improving patient care.Melanoma, a highly aggressive form of skin cancer, is characterized by rapid progression and high mortality. Recent advances in molecular pathogenesis have revealed genetic and epigenetic changes driving melanoma development. This review focuses on the molecular mechanisms in melanoma genesis, highlighting mutations in genes such as *BRAF*, *NRAS*, *c-KIT*, and *GNAQ/GNA11* that affect critical signaling pathways. The evolution of diagnostic techniques, including genomics, transcriptomics, liquid biopsies, and molecular biomarkers, has improved early detection and prognosis. Therapeutic advancements include targeted therapies and immunotherapies, which have transformed patient outcomes. The review discusses the efficacy, challenges, and prospects of these treatments, emphasizing the importance of personalized medicine and evidence-based therapy selection. Novel treatment strategies, such as neoantigen vaccines, adoptive cell transfer, microbiome interactions, and nanoparticle-based combination therapy, are explored, along with the potential of DNA damage response inhibitors. The integration of emerging therapies into clinical practice is crucial for overcoming resistance and improving patient care.