Diffuse low and intermediate-grade gliomas (World Health Organization grades II and III gliomas) are cancerous brain tumors that typically occur in younger adults. These diseases have highly variable clinical behavior that is not adequately predicted on the basis of state-of-the-art diagnostic methods, which include looking at the tumor cells under the microscope to classify the diseases into astrocytomas, oligodendrogliomas and oligoastrocytomas. This diagnostic strategy can be subjective and can vary depending on the observer, contributing to the uncertainty during diagnosis. Some gliomas grow slowly; others quickly progress to very aggressive glioblastomas, and it is often unclear which patient will have which course of the disease. For the current study, members of The Cancer Genome Atlas Analysis Working Group took a crack at categorizing lower-grade gliomas using an integrated profile DNA and RNA sequences, along with other genomic analyses on samples from almost 300 individuals with lower-grade gliomas. The approach established more reliable classifications than the traditional microscopy approach. In particular, this combined molecular data classified low and intermediate forms of astrocytoma, oligoastrocytoma, and oligodendroglioma into three main molecular groups, largely defined by genetic features, including the IDH1/2 gene mutations, chromosome 1 and 19 co-deletion, and TP53 mutations. These results point to the possibility of classifying lower-grade gliomas in the clinic using a small set of informative biomarkers that can be examined using tumor DNA. Integrated molecular profiles for tumor and matched normal samples from 293 individuals with grade II and grade III glioma also provided a clearer look at molecularly defined subtypes containing these alterations. In particular, tumors containing IDH mutations could further be sub-classified depending on the presence or absence of the chromosome 1 and 19 co-deletion. Oligodendrogliomas almost always contained both IDH mutations and the 1p/19q deletion, suggesting that these mutations may molecularly define that subtype. The most commonly mutated genes in that subtype included NOTCH1, FUBP1, and CIC. The IDH-mutant, 1p/19q-deleted tumors also tended to contain alterations that affected the region that regulates the amount of the telomerase-coding gene TERT, boosting expression and activity of this molecule, important for cancer cell divisions. On the other hand, tumors from the astrocytoma subtype frequently carried IDH mutations in combination with TP53 and the ATRX gene glitches, while tumors lacking IDH mutations defined an aggressive subtype with some genetic and clinical similarities to the most aggressive brain tumor, glioblastoma. The study will inform how doctors define and treat grade II and grade III gliomas.