The IDH-wt adult diffuse astrocytoma or glioblastoma (GBM) is the most frequent and aggressive malignant tumor in the central nervous system (CNS). Affecting people usually over the age of 55 years old, it is one of the most lethal cancers with estimated 5-year survival rates below 5%, median overall survival only ~21 months, even following aggressive treatment, and an almost 100% recurrence rate. The current standard treatment includes complete surgical resection, followed by radiation, and concurrently amplified with chemotherapy, as well as multimodal combinations of all the above. However, due to the GBM’s intratumoral and inter-tumoral genetic heterogeneity and its highly immunosuppressive and immune-evasive microenvironment, there have been significant resistance to therapy and therefore low efficacy of any possible treatment. In this chapter, we reviewed the latest progress in preclinical and clinical research involving the current immunotherapeutic strategies which employ oncolytic viruses, several types of vaccines, chimeric antigen receptor-T cells, and checkpoint inhibitors in order to target glioblastoma and its microenvironment. While results may vary, most immunotherapeutic strategies are able to target the tumor microenvironment, and with further trials we can anticipate their reactivation of the patients’ immune response against tumors, in order to limit tumor proliferation and eventually eradicate the tumor. Since GBM remains one of the most lethal cancers, it is important to overcome the methods of traditional medicine that rely heavily on the Stupp protocol and seek new and modern alternatives, treatments tailored to each individual, that target specific tumor cells.