Neoantigen-based cancer vaccines represent an innovative and promising approach in precision oncology, using tumor-specific mutations to create tailored immune responses against cancer. These vaccines have shown considerable potential in recent clinical trials, demonstrating safety, feasibility, and the ability to elicit strong immune activity with promising clinical outcomes across various cancer types. This review examines the latest developments in neoantigen-based vaccines, their current challenges, and the future strategies required to integrate these vaccines into mainstream cancer treatment, highlighting their transformative potential in advancing personalized medicine. Clinical trials have demonstrated the safety and feasibility of this approach, with results showing robust immune activation, including the generation of neoantigen-specific CD4+ and CD8+ T cell responses, as well as clinical benefits such as prolonged progression-free survival and tumor regression in some patients. Despite these successes, challenges such as tumor heterogeneity, variability in immune responses, and immune evasion mechanisms remain barriers to widespread implementation. Combining neoantigen vaccines with other therapies, such as checkpoint inhibitors or adoptive T cell therapies, has shown potential to overcome these issues.