Gliomas are the most common primary brain tumors and the highest-grade glioma, glioblastoma (GBM), is arguably the most aggressive tumor type, with virtually no long-term survivors. Patients with GBM are treated with radiotherapy, chemotherapy, surgery, and tumor treating fields. Despite initial response, all tumors recur as incurable lesions; there is an urgent need for novel therapeutic approaches for this patient group. I posit that a better understanding of how radiotherapy and hypoxia re-educates the brain microenvironment will provide new treatment strategies for aggressive gliomas. Recent advances have established a central role for the tumor microenvironment (TME) in determining the therapeutic response of GBM cells, and my lab has demonstrated that standard of care radiotherapy of the primary tumor can shape the microenvironment to generate tumorsupportive conditions in the recurrent tumor. These findings suggest that there is untapped potential in targeting the irradiated microenvironment. We aim to explore and exploit the recurrent GBM TME by functionally characterizing heterotypic cell-cell and cell-matrix interactions unique to the recurrent GBM TME in order to define supportive and restrictive elements, and identifying and exploiting reversible stromal radiation responses and leveraging novel therapeutic opportunities unique to the irradiated brain.