This narrative review critically examines the intrinsic biological determinants of prognosis in HGGs, as delineated in the 2021 World Health Organization Classification of Tumors of the Central Nervous System, which differentiates glioblastoma (IDH-wildtype), astrocytoma (IDH-mutant), and oligodendroglioma (IDH-mutant, 1p/19q-codeleted) based on distinct molecular signatures. Here, IDH2 is linked to glioblastoma.