Meningiomas arising from the meningothelial lining of the central nervous system are the most common primary intracranial tumors, and a significant cause of neurologic morbidity and mortality. There are no effective medical therapies for meningioma patients, and new treatments have been encumbered by limited understanding of meningioma biology. The aim of this study was to understand the biology underlying meningioma DNA methylation groups, and identify novel therapeutic strategies to treat meningioma patients.Illumina 850K DNA methylation profiling was performed on a discovery cohort of 200 meningiomas (median follow-up 6.3 years) and an external validation cohort of 365 meningiomas (median follow-up 5.3 years) from patients who were treated at 2 independent, international institutions from 1991 to 2019 (69% WHO grade 1, 25% WHO grade 2, 6% WHO grade 3). RNA sequencing was performed on the discovery cohort, and single-cell RNA sequencing was performed on 8 meningiomas to define the cellular architecture of meningiomas across DNA methylation groups. Targeted DNA sequencing (n = 65), H3K27ac ChIP sequencing (n = 25), whole exome sequencing (n = 25), and immunohistochemistry (n = 87) were used to validate novel biologic mechanisms underlying DNA methylation groups.Unsupervised hierarchical clustering of DNA methylation profiles revealed 3 DNA methylation groups of meningioma with distinct clinical outcomes in the discovery cohort, which was validated in the external cohort using a multi-class support vector machine classifier. Merlin-intact meningiomas (34%) had the best outcomes and were distinguished by a novel tumor suppressor function of NF2/Merlin regulating glucocorticoid signaling and apoptosis. Immune-enriched meningiomas (38%) had intermediate outcomes and were distinguished by immune cell infiltration, HLA expression, and lymphatic vessels. Hypermitotic meningiomas (28%) had the worst outcomes and are distinguished by convergent genetic mechanisms misactivating the cell cycle, including CDKN2A/B loss, FOXM1 overexpression, and USF1 gain. Consistently, we found cell cycle inhibitors blocked Immune-enriched and Hypermitotic meningioma growth in cell culture, organoids, xenografts, and patients.Here we integrate genetic, epigenetic, transcriptomic, biochemical, and single-cell approaches to find that meningiomas are comprised of 3 DNA methylation groups with distinct clinical outcomes and biological drivers. We validate our results using mechanistic and functional studies in cells, organoids, xenografts, and patients to elucidate novel mechanisms and identify therapeutic vulnerabilities underlying the most common primary intracranial tumor. Our results establish a framework for understanding meningioma biology, and provide preclinical rationale for new meningioma treatments.A. Choudhury: None. S. Magill: None. C.D. Eaton: None. B.C. Prager: None. W.C. Chen: None. K. Seo: None. C. Lucas: None. J. Villanueva-Meyer: None. H. Vasudevan: Research Grant; Children's Tumor Foundation. Patent/License Fees/Copyright; Genentech, Eli Lilly. S.J. Liu: None. M.A. Cady: None. M.Y. Zhang: None. S.E. Braunstein: Advisory Board; Radiation Oncology Questions, LLC.N.A. Oberheim: None. A. Perry: None. D.A. Solomon: None. J. Costello: None. M.W. McDermott: None. J.N. Rich: None. D. Raleigh: None.