Alessia Ciafarone, Paola Palumbo
Chemotherapy has profoundly shaped modern oncology, evolving from early cytotoxic approaches to biologically informed strategies. In glioblastoma (GBM), the highly aggressive primary brain tumor, precision medicine does not rely on the identification of a single crucial oncogenic driver but integrates biologically informed stratification strategies to predict treatment response, resistance, and therapy-induced adaptation. This review recapitulates the historical milestones of chemotherapeutic development in neuro-oncology, with particular emphasis on GBM. As the main chemotherapeutic agent currently used in GBM, temozolomide (TMZ) initially represented a major therapeutic breakthrough; however, its clinical use has progressively unveiled the biological and clinical limitations of conventional cytotoxic paradigms. While TMZ exerts antitumor activity through DNA damage-induced apoptosis, accumulating experimental evidence indicates that it may also elicit adaptive responses, ultimately supporting tumor progression and therapy resistance. By integrating historical milestones with recent molecular understanding, this review highlights how improved knowledge of therapy-induced adaptations may inform emerging precision medicine strategies in GBM, underscoring the need for tailored treatments to overcome tumor heterogeneity and adaptive responses.