The successful eradication of multiple tumor types, often in a durable manner, has recently validated the bona fide potential of an effectively mobilized immune response as a cancer therapy. Critical questions at present, therefore, include deciphering why some patients respond while others do not, as well as why certain cancers respond while others like glioblastoma do not. Glioblastoma remains a major unmet need in medical oncology and is considered incurable with less than 10% of patients surviving five years from diagnosis. Hallmark phenotypic features of glioblastoma including aberrantly activated cell proliferation, survival, invasion, angiogenesis, and treatment resistance are linked with multiple adaptive and supportive mechanisms culminating in formidable heterogeneity across and within individual tumors. Similarly, the complex adaptive abilities of glioblastoma tumors to abrogate anti-tumor immune responses are multifaceted yet integrated. Not unexpectedly, results of recent advanced clinical trials with single-agent immunotherapeutics for glioblastoma have been negative although some early stage studies and anecdotal cases have generated encouraging results. The application of immunotherapies for glioblastoma currently finds itself therefore at a pivotal crossroads. Critical to mapping a path forward will be the systematic characterization of the immunobiology of glioblastoma tumors utilizing currently available, state of the art technologies. Therapeutic approaches aimed at driving effector immune cells into the glioblastoma microenvironment as well as overcoming immunosuppressive myeloid cells, physical factors, and cytokines, as well as limiting the potentially detrimental, iatrogenic impact of dexamethasone, will likely be required for the potential of anti-tumor immune responses to be realized for glioblastoma.