High grade gliomas, the most frequent and most malignant brain cancers, grow rapidly and infiltrate the cerebrospinal axis causing deficits in cognition, mobility, balance or speech and are typically resistant to radiation and chemotherapy. Despite recent progress, WHO grade III and IV gliomas still represent a great challenge in oncology, with overall poor outcomes and inevitable lethality. While radiotherapy and temozolomide are considered the standard first-line approach for therapy of newly diagnosed malignant gliomas, the treatment protocols for recurrent tumors remain ill-defined. Increasing evidence suggests that tumors of the central nervous system are derived from proliferatively active neural stem cells residing in defined neuropoietic niches of the adult brain. These cancer stem cells, also identified in other tumors, provide a reservoir of cells with self-renewal capabilities, can maintain the tumor by generating differentiated non-stem tumor cells and are responsible for recurrences after ablative neurosurgical therapy and chemoradiotherapy. The only way to successfully control recurrent malignant gliomas and even hope for a cure in the future is by combining standard chemotherapy with immunotherapy. Despite the apparent improvements of current treatments, it should be realized that the characteristic brain tumor niche may provide recurrent gliomas an "escape mechanism" from anticancer treatments. Thus, the use of targeted molecular therapy drugs may effectively inhibit or at least slow down cancer stem cell proliferation and stop the brain microenvironment from allowing furtive invasion and proliferation of highly aggressive malignant gliomas.