BACKGROUND: Glioblastoma multiforme (GBM), the most common and aggressive malignant brain tumor, almost always recurs despite aggressive treatments combining surgery, radiation, and chemotherapy. Thus, understanding how individual tumors evolve in response to the standard treatments is essential for improved patient care. METHODS: Here, we describe our genomic analysis of the paired pre- and post-treatment tumors from 20 glioblastoma patients. RESULTS: Tumors also acquired diverse alterations that appeared to contribute to treatment resistance, such as the increased expression of CDK4/6 in the IDH1-mutated tumors and novel EGFR and MET mutations, in addition to TP53, RB1, and APC alterations that were previously implicated with treatment resistance. CONCLUSIONS: The patient-specific genomic alterations that arise following treatments may represent superior therapeutic targets for recurrent GBMs. This work suggests that assessing genomic changes in individual tumors after recurrence is paramount for precision neuro-oncology. SECONDARY CATEGORY: Tumor Biology.