Individualized neoantigen-directed therapy represents a groundbreaking approach in melanoma treatment that leverages the patient's own immune system to target cancer cells. This innovative strategy involves the identification of unique immunogenic neoantigens (mutated proteins specific to an individual's tumor) and the development of therapeutic vaccines that either consist of peptide sequences or RNA encoding these neoantigens. The goal of these therapies is to induce neoantigen-specific immune responses, enabling the immune system to recognize and destroy cancer cells presenting the targeted neoantigens. This individualized approach is particularly advantageous given the genetic heterogeneity of melanoma, which exhibits distinct mutations among different patients. In contrast to traditional therapies, neoantigen-directed therapy offers a tailored treatment that potentially reduces off-target side effects and enhances therapeutic efficacy. Recent advances in neoantigen prediction and vaccine development have facilitated clinical trials exploring the combination of neoantigen vaccines with immune checkpoint inhibitors. These trials have shown promising clinical outcomes, underscoring the potential of this personalized approach. This review provides an overview of the rationale behind neoantigen-directed therapies and summarizes the current state of knowledge regarding personalized neoantigen vaccines in melanoma treatment.