Abstract <p>Although melanoma is one of the most aggressive skin cancers with limited treatment options at advanced stages, immune checkpoint inhibitors and targeted therapies have led to meaningful clinical progress. Cancer vaccines have long been investigated as a strategy to activate anti-tumor immunity in melanoma, with early approaches primarily focused on shared tumor-associated antigens (TAAs). However, these initial efforts were constrained by limited immunogenicity, central and peripheral tolerance to self-antigens, suboptimal antigen selection, and logistical challenges. Recent advances in cancer genomics, bioinformatics, vaccine engineering, and immunotherapy have catalyzed a paradigm shift toward vaccines targeting tumor-specific antigens, particularly patient-specific neoantigens arising from somatic mutations. In this review, we summarize both historical and contemporary developments across key melanoma vaccine platforms, including peptide-based, dendritic cell, whole-cell, viral, bacterial, mRNA, and nanoparticle-based vaccines. We highlight preclinical and clinical findings that inform antigen selection, the role of adjuvants and delivery systems, and the rationale for combinatorial strategies incorporating immune checkpoint inhibitors or tumor microenvironment modulators. While whole-cell and vector-based vaccines provide broad antigenic coverage, neoantigen-based and nanoparticle-enabled vaccines offer highly specific, personalized, and potentially scalable approaches that align with precision immuno-oncology. Ongoing challenges include manufacturing complexity and cost, tumor immune evasion and resistance mechanisms, and the need for rationally designed combination regimens to maximize durable clinical benefit.</p>