Abstract Glioblastoma (GBM) comprises >50% of all brain tumors in adults and is the most malignant form with a 5-year patient survival rate of 3.3%. Standard-of-care treatment involves maximal surgical resection followed by radiation and chemotherapy (temozolomide); however, as the poor survival rate indicates, these treatments have not been effective in preventing disease progression. Glioblastomas are highly heterogeneous with a small subpopulation of neural stem-like cells notorious for their resistance to conventional therapy and known to be responsible for tumor recurrence and patient death. Therapies that target tumor cells as well as glioma stem cells (GSCs), while sparing normal cells, would be highly beneficial for these patients. The unique capacity of mammalian olfactory epithelium in continuous replacing its olfactory receptor neurons by physiological turnover and following injury throughout life has been attributed to the olfactory ensheathing cells (OECs), a glial cell type that closely accompany the axons as they grow from the olfactory epithelium into the olfactory bulb. OECs migrate from the peripheral nervous system to the central nervous system (CNS), a critical process in the development and maintenance of the olfactory system and axonal extension after injury in neural regeneration. OECs release diffusible factors to attract neural progenitors into the rostral migratory stream and regulate their proliferation and differentiation and to differentiate neural stem cells leading to neurite extension. Owing to their strong ability to myelinate and guide axonal outgrowth, neuroprotective role, as well as their immunomodulatory and phagocytic properties, the therapeutic potential of OECs was evaluated against different neurological pathologies in the clinic and as a carrier for therapeutic transgene to glioma cells in culture, but their tropism and effect against gliomas in vivo were not studied. Recently, we showed for the first time that autologous transplantation of mouse OECs can target and deliver therapeutic transgenes to brain tumors upon intranasal administration, the natural route of OECs to CNS. In this proposal, we will build on this study and evaluate the potential use of OECs for glioblastoma stem cell therapy by regulating proliferation and/or differentiation of GSCs, making them susceptible to conventional therapies, reversing immune supression and activating anti-tumor immunity.