||Meningiomas are the most common primary brain tumors, accounting for 36.6% of all tumors with ∼20,000 cases annually in the U.S. Although 65-80% of cases are benign (World Health Organization [WHO] Grade I), recurrence over a long period can be seen, especially for subtotal resections and higher-grade tumors (II and III). Radiotherapy is a common primary or adjuvant therapy, but its mechanisms of action in the setting of distinct subtypes of meningioma remain unknown. Hypoxia-inducible factor 1 (HIF1) plays a key role in cellular response to oxygen tension, modulates multiple downstream genes, controls tissue vascularization, and may serve as a resistance-promoting mechanism in tumors. The aim of this study was to evaluate the clinical impact of the HIF1-signaling pathway in meningioma characterization as well as the impact of radiotherapy on meningiomas in the setting of HIF1 knockout. Clinical samples from patients with meningiomas, primary derived cell lines (GAR, JEN, SAM, MCT, BSH, IOMM-LEE), and HIF1 generated knockouts (GAR-1589) were utilized. Multiple immunohistochemical markers and a fractal-based microvascularity quantification showed that Grade I meningiomas ≥3 cm showed greater staining for MIB and von Willebrand Factor as well as an average 19-month shorter survival. In addition, a MIB index ≥3 showed high specificity (82.5%) but not sensitivity (36%) for predicting progression-free survival. Cell proliferation and apoptosis in response to radiation doses depended on cell density, HIF1A mutational status, and oxygen tension. Higher plated densities of cells showed resistance to radiation for various primary meningioma cell lines. GAR cells demonstrated greater response to high-dose radiation than GAR-1589 cells in 2D and 3D cultures, while neither cell line responded to fractionated radiotherapy. Hypoxic environments reduced the efficacy of radiation, in fact showing increased cell proliferation with low doses of radiation. GAR-1589 cell, however, showed greater increases in cell apoptosis during radiotherapy in normoxic environments than GAR cells. Multimodal imaging using tumor bioluminescence, positron emission tomography tracers, and MRI showed potential for evaluating various characteristics of primary brain tumors noninvasively using an orthotopic rodent model. These results offer some correlation clinically and experimentally regarding the importance of HIF1 and tumor resistance.