Background: Genomic profiling of gliomas is vital to ensure diagnostic accuracy, inform prognosis, and identify therapeutic options for primary and recurrent tumors. The integration of genomic biomarkers into brain tumor classification has advanced the development of molecularly stratified clinical trials and the need to characterize tumors by genomic signature. Methods: Comprehensive genomic profiling (CGP) was performed on FFPE material from 6304 consecutive cases of pediatric and adult brain tumors initially diagnosed by submitting institutions based on histology. We analyzed tumors via CGP in 395 cancer-associated genes (including IDH1/2) and for 1p/19q codeletion using a validated algorithm. Results: Of 6304 brain tumor samples, known IDH point mutations included 1182 IDH1 R132, 50 IDH2 R172, and 1 IDH2 R140 variants. In the IDH-mutant cohort, 1p/19q codeletion was detected in 72% (260/363) of histologically defined oligodendrogliomas (ODGs), 21% (17/82) of oligoastrocytomas (OAs), 6% (22/360) of glioma (NOS, not otherwise specified), 4% (2/50) of gliosarcomas, 3% (26/859) of astrocytomas (NOS), and 1% (32/3200) of glioblastomas. ODG with 1p/19q loss were enriched for TERT, CIC, and FUBP1 alterations, whereas 1p/19q intact tumors were enriched for TP53 and ATRX alterations. Actionable alterations in ODG included 8% (29/363) with high tumor mutational burden (potential immunotherapy responsiveness) and 15% (56/363) with PIK3CA mutation. Analysis of OA (mixed glioma) revealed genomic subtypes similar to well-defined gliomas including ODGs (IDH-mutant, 1p/19q loss, TERT, CIC, FUBP1), diffuse astrocytomas (IDH-mutant, TP53, ATRX), and high-grade gliomas (IDH-wild-type, EGFR, NF1). Conclusions: Using co-occurring IDH mutation and 1p/19q codeletion as the diagnostic signature of ODG, we show that as many as 25% may be misclassified on morphologic criteria alone. OAs exhibit genomic features of defined glioma subtypes, suggesting CGP may provide diagnostic clarity in this setting. This study highlights how CGP can improve diagnostic accuracy and provide additional treatment options for patients.