The development of immunotherapy has revolutionized the landscape of cancer treatment. Personalized neoantigen vaccines are attractive systemic immunotherapies that trigger specific T-cell responses against highly specific neoantigens, and activate and expand helper and cytotoxic T-lymphocytes to enhance anti-tumor immunity. Based on the rapid development of bioinformatics and the continuous update of sequencing technology, cancer immunotherapy with tumor neoantigens has made promising breakthroughs and progress. Researchers are exploring the value of neoantigen vaccines alone or in combination in different tumor types. We provide an overview of the complex process that is necessary to generate a personalized neoantigen vaccine, discuss the current status of clinical studies and application testing personalized neoantigen vaccines in patients with cancer and future perspectives on this novel, personalized approach to immunotherapy.