The Cancer Genome Atlas Research Network conducted a comprehensive, integrative genomic analysis of 293 adult lower-grade gliomas (World Health Organization grades II and III) to better understand their clinical behavior and molecular classification. The study used exome sequencing, DNA copy number, DNA methylation, messenger RNA expression, microRNA expression, and targeted protein expression data. Unsupervised clustering of these data revealed three distinct molecular subtypes of lower-grade gliomas, which were more accurately captured by *IDH*, 1p/19q codeletion, and *TP53* status than by histologic class. Patients with lower-grade gliomas that were wild-type for *IDH* had shorter overall survival compared to those with *IDH* mutations, and these tumors showed genomic and clinical similarities to primary glioblastoma. The findings suggest that molecular classification based on *IDH*–1p/19q status can improve diagnostic accuracy and guide clinical management.The Cancer Genome Atlas Research Network conducted a comprehensive, integrative genomic analysis of 293 adult lower-grade gliomas (World Health Organization grades II and III) to better understand their clinical behavior and molecular classification. The study used exome sequencing, DNA copy number, DNA methylation, messenger RNA expression, microRNA expression, and targeted protein expression data. Unsupervised clustering of these data revealed three distinct molecular subtypes of lower-grade gliomas, which were more accurately captured by *IDH*, 1p/19q codeletion, and *TP53* status than by histologic class. Patients with lower-grade gliomas that were wild-type for *IDH* had shorter overall survival compared to those with *IDH* mutations, and these tumors showed genomic and clinical similarities to primary glioblastoma. The findings suggest that molecular classification based on *IDH*–1p/19q status can improve diagnostic accuracy and guide clinical management.