Gliomas exhibit high proportions of glioma stem cells (GSCs), anoikis resistance, increased brain parenchyma invasion, and resistance to therapy with high recurrence. GSCs display protective autophagy, a self-mediated lysosomal degradation process that balances sources of energy at critical times of stress. Protective autophagy in GSCs promotes resistance to anoikis, programmed death resulting from growth in an anchorage-independent manner. MDA-9 is critical in maintaining protective autophagy in GSCs, thereby contributing to anoikis-resistance. MDA-9 regulates critical molecules, including BCL2 and EGFR, which control autophagy. A link between MDA-9 and protective autophagy and anoikis-resistance identifies an Achilles’ heel of glioblastoma multiforme that may be exploited to define enhanced therapies with improved prognosis and decreased recurrence. Accordingly, targeting MDA-9 may represent a viable therapeutic strategy for glioblastoma multiforme.