<p>Glioblastoma multiforme (GBM) is the most prevalent invasive CNS tumor, with a high incidence rate and a high likelihood of recurrence in most patients. Despite available treatments, recurrent glioblastoma (rGBM) exhibits growing resistance to chemotherapy and radiotherapy, which necessitates the development of newer methods of treatment. Peptide vaccines, a type of cancer immunotherapy, have recently attracted attention as a potentially practical therapeutic approach because they target tumor-associated or tumor-specific antigens to generate an effective immune response against cancer cells. These vaccines have been included in several clinical trials, demonstrating their safety and effectiveness by eliciting protective immune responses. However, peptide vaccines for glioblastoma face challenges due to the complex nature of intracranial brain tumors that require innovative approaches and in-depth research to increase their efficacy. The main topics covered in this article include immunological inhibitors and immune characteristics of the CNS and GBM, the basis of immunity, and the significant results of clinical trials of peptide vaccine therapy for GBM. Additionally, it examines the potential causes of the low effectiveness of these vaccines and recommends future research to address the specific challenges associated with immunotherapy in GBM. The evaluation of preliminary phase studies and phase III clinical trials will provide insights into potential immunological responses, biosecurity precautions, and clinical outcomes, guiding future vaccination initiatives to promote higher effectiveness.</p>