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Primary brain tumors, particularly glioblastoma, are associated with significant morbidity and are often recalcitrant to standard therapies. In recent years, brain tumors have been the focus of large-scale genomic sequencing efforts, providing unprecedented insight into the genomic aberrations and cellular signaling mechanisms that drive these cancers. Discoveries from these efforts have translated into novel diagnostic algorithms, biomarkers, and therapeutic strategies in Neuro-Oncology. However, the cellular mechanisms that drive brain tumors are heterogeneous and complex: applying this new knowledge to improve patient outcomes remains a challenge. Efforts to characterize and target these molecular vulnerabilities are evolving.