Brain cancers pose a unique challenge for immunotherapy due to the classical view of the central nervous system (CNS) as an immune-privileged site and the presence of immunosuppressive factors. Nevertheless, encouraging results from immunotherapy in other forms of cancer have spurred research on immunotherapeutic approaches to brain cancer as well. These methods include the utilization of monoclonal antibodies, immunotoxins, chimeric antigen receptor (CAR) T cells and adoptive T cell therapy, virotherapy, cancer vaccines, and radioimmunotherapy. The necessity of developing such approaches is further highlighted by the fact that despite years of research on treating glioblastoma (GBM), the most common brain cancer in adults, GBM remains a grim diagnosis. In this chapter, we delve deeper into the challenges faced by immunotherapy in the treatment of glioblastoma, present the various immunotherapeutic approaches currently under study for the treatment of GBM, and discuss the potential advantages and possible pitfalls of each method.