PURPOSE OF REVIEW: Glioblastoma is the most aggressive and treatment-resistant primary brain tumor in adults. Given its clinical severity and biological complexity, research efforts are focused on understanding and targeting intratumoral heterogeneity, adaptive resistance, drug delivery barriers, and the immunosuppressive tumor microenvironment. This review highlights emerging therapeutic approaches for the treatment of glioblastoma including advances in radiation planning, molecularly targeted therapy, immunotherapy, blood-brain barrier modulation, and neuronal signaling. RECENT FINDINGS: Radiation therapy remains a cornerstone of glioblastoma treatment, and advances in image-guided planning are being developed to refine treatment margins and improve tolerability without compromising efficacy. Blood-brain barrier permeability is being improved through device-assisted approaches, including focused ultrasound in combination with systemic therapies. Molecularly targeted and immunotherapeutic approaches continue to be evaluated, increasingly with biomarker-informed strategies to optimize patient selection. In parallel, drug repurposing, neuronal modulation, and metabolic interventions have shown promising preclinical and retrospective signals and are moving towards prospective studies. Interventions to improve quality of life are also underway with early palliative care showing significant impact for patients with glioblastoma. SUMMARY: As the field moves towards tailored and precision-guided approaches, combination strategies remain central to addressing the multiple mechanisms by which glioblastoma evades treatment.