Glioblastoma multiforme (GBM) is a highly aggressive and invasive type of primary brain tumor. Despite maximal safe surgical resection followed by concurrent adjuvant chemotherapy and radiotherapy, the clinical prognosis is grim, with only marginal prolongation of survival and poor quality of life. Median survival time is 15 months. This review will discuss the pathogenesis of GBM, diagnostic challenges, clinical evaluation, imaging, genomics and current therapeutic options. The intrinsic immunosuppressive properties of GBM and additional adverse changes in immune surveillance and the systemic immune environment brought about by chemoradiotherapy will be addressed. GBM stem cell properties and their role in local recurrence and preclusion of cure will be covered. We will discuss the limited penetration of the blood-brain barrier by therapeutics as a major obstacle in treatment. Advances in novel therapeutic strategies using personalized approaches, cell-based therapies, tumor vaccines and targeted drug delivery will be considered.