The field of cancer immunotherapy has moved forward drastically in the past 20 years, since many tumorassociated antigens (TAA) have been identified. Although various approaches for therapeutic cancer immunotherapies, including peptide-based vaccines, have been developed and clinically examined, the complexity and diversity of tumor cell characteristics and host immune cell repertoires seem to limit the therapeutic efficacy of this treatment modality. Considering the diversity of immune responses against heterogeneous tumor cells, tailored selections of vaccine antigens appropriate for individual patients could be a rational approach for developing effective cancer vaccines. We have developed a novel immunotherapeutic approach called personalized peptide vaccine (PPV), in which a maximum of four human leukocyte antigen (HLA)-matched vaccine peptides were selected based on the pre-existing host immunity before vaccination. We conducted a series of phase I and phase II clinical trials of PPV, which have shown better antigen-specific immune responses and promising clinical outcomes in patients with various types of advanced cancers. Further randomized phase III trials would be recommended to prove the clinical benefits of PPV. In addition, novel biomarkers for selecting patients who would benefit most from PPV remain to be identified.