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Glioblastoma (GBM) is the most aggressive form of primary brain cancer, with 5-year survival rates of less than 5%. Clinical management of GBM has not changed in the last 15 years, and current treatment approaches combine surgical resection, followed by radiotherapy and chemotherapy. Tragically, tumour recurrence is inevitable. Still, very little is known about how tumours evolve in response to therapy and become treatment resistant. In 2019, The Glioma Longitudinal AnalySiS (GLASS) consortium curated extensive, publicly accessible genomic profiling data captured from matched primary and recurrent tumours across 222 patients, along with comprehensive clinical annotations. Recently, this longitudinal genomic data resource was expanded by integrating matching transcriptomic and genomic data from 304 adult patients with isocitrate dehydrogenase (IDH)-wild-type and IDH-mutant glioma captured at two or more time points (Varn et al., 2022). This has enabled new insights into the dynamic changes in transcriptional programs, cellular compositions and microenvironment interactions within these brain tumours. In this commentary, we will focus on recurrent high-grade IDHwt and the implications of these findings for targeting tumour-microenvironment interactions that may pave new pathways for developing therapies for this type of brain tumour.