Glioblastoma (GBM) is the most common and aggressive primary central nervous system malignancy. Significant resistance to therapeutic intervention is a core feature of GBM that drives tumor recurrence and underlies the remarkably poor clinical outcomes associated with this disease. This review explores the therapeutic strategies and molecular pathways involved in GBM. Therapy resistance in GBM depends on multiple interconnected macrostructural and biomolecular mechanisms, including aggressive and diffuse invasion, tumor microtube network formation, stem-like cell enrichment, selective neurovascular permeability, an immunosuppressive microenvironment, and a high degree of inter- and intra-tumoral heterogeneity. Collectively, these pathobiological features insulate specific tumor compartments and maintain GBM viability despite significant treatment-induced cellular stress. While there is enthusiasm for addressing GBM therapeutic resistance, the scale of the challenge remains immense. The identified resistance mechanisms extensively interact and can compensate for single-target assaults. Emerging overlaps between neuro-oncology and developmental neurobiology additionally suggest that GBM may exploit therapeutic resistance mechanisms yet to be identified, functioning beyond the current scientific understanding. Thus, the scope and diversity of this problem demand a comprehensive therapeutic approach capable of targeting multiple interacting mechanisms of therapeutic resistance.