Immunotherapy is emerging as a powerful approach to treating cancer. Antagonists of immune checkpoint regulators, T lymphocytes engineered to recognize tumor antigens, and vaccines that amplify tumor-specific lymphocytes are being tested against a variety of human malignancies. Although some remarkable successes have been reported, only a subset of patients respond to these therapies, and the mechanisms that underlie resistance are poorly understood. Pediatric brain tumors, in particular, have not yet benefited from immunological targeting. We are studying the mechanisms brain tumors use to evade the immune system and suppress immune responses, and developing therapeutic strategies to overcome these mechanisms. We are also using genomic and proteomic approaches to identify antigens that might represent novel targets for vaccines, CAR T cells and natural killer cells. Finally, we are “humanizing” our PDX models so we can explore interactions between the immune system and patient-derived tumor cells. By increasing the immunogenicity of tumor cells and enhancing anti-tumor immune responses, we hope to bring the benefits of immunotherapy to medulloblastoma patients.