Immune checkpoint inhibitors have significantly improved the prognosis of patients with melanoma, but primary and acquired resistance have led to a bottleneck in treatment. The binding of T-cell receptors to tumor antigens is the key point for immunotherapy. Neoantigens are newly formed antigens generated by tumor cells as a result of various tumor-specific alterations. Neoantigens, identifiable as foreign entities, have the capacity to initiate an immune response unfettered by central and peripheral tolerance mechanisms. This distinctive characteristic renders them highly promising targets in the realm of cancer therapy. Vaccines targeting tumor neoantigens, adoptive cell transfer, and antibody-based therapies can effectively enhance and expand tumor-specific immune responses, promoting T-cell recognition and elimination of tumors, thereby breaking through current treatment bottlenecks. This article discusses the current status, recent advancements, clinical challenges, and future directions in the personalized treatment of melanoma based on neoantigens.