The ability of the immune system to recognize malignant cells has opened the door to development of tumor vaccines to treat or prevent various types of cancer. In the era of molecular biology, the tumor antigens recognized by the immune system have been identified, allowing the generation of subunit vaccines that may improve safety and efficacy compared with more crude vaccines such as irradiated tumor cells and tumor cell lysates. Synthetic peptides corresponding to defined antigenic epitopes for tumor-reactive lymphocytes represent one of the new types of vaccines currently being developed to treat or prevent various types of malignant disorders. The design of peptide-based vaccines to stimulate antitumor T-cell responses has many attractive features such as ease of manufacturing and characterization (ie, quality control), as well as an excellent safety profile in past clinical studies. However, ambiguous results from initial clinical trials indicate that these vaccines are far from optimal and that considerable efforts for their optimization lie ahead. We attempt to address the 8 most important challenges we currently face for developing peptide-based vaccines that would effectively induce immune responses leading to antitumor effects.