Glioblastoma (GBM) remains resistant to most conventional treatments, with limited effective new therapies in the past three decades. New approaches to drug delivery and clinical trial design are needed. The blood–brain barrier (BBB) and tumor microenvironment pose significant challenges for GBM treatment. Novel strategies include drug designs like nanoparticles and antibody–drug conjugates, delivery methods such as convection-enhanced and intra-arterial delivery, and techniques to enhance drug penetration, such as focused ultrasound and laser interstitial thermal therapy. Future directions include combination therapy, neoadjuvant and window-of-opportunity approaches, and adaptive platform and basket trials for clinical trial design. New GBM treatments should account for the BBB and immunosuppression by improving drug delivery, combining treatments, and integrating novel clinical trial designs. Current standard treatment for GBM includes surgery, radiotherapy, and chemotherapy. However, these treatments often fail to provide long-term tumor control. GBM is immunosuppressive, leading to local and systemic immune suppression. Immunotherapies have shown limited success in GBM due to the tumor's immunosuppressive environment. Novel therapeutics include oncolytic viruses, CAR T cells, and vaccines. The BBB restricts drug penetration, limiting therapeutic effectiveness. Strategies to overcome this include BBB-penetrant drugs, nanoparticles, antibody–drug conjugates, and radioimmunotherapy. Novel drug delivery methods such as intra-arterial delivery, convection-enhanced delivery, and laser interstitial thermal therapy are being explored. Focused ultrasound can disrupt the BBB to enhance drug delivery. Clinical trials are needed to evaluate these approaches, with a focus on combination therapies and adaptive trial designs.Glioblastoma (GBM) remains resistant to most conventional treatments, with limited effective new therapies in the past three decades. New approaches to drug delivery and clinical trial design are needed. The blood–brain barrier (BBB) and tumor microenvironment pose significant challenges for GBM treatment. Novel strategies include drug designs like nanoparticles and antibody–drug conjugates, delivery methods such as convection-enhanced and intra-arterial delivery, and techniques to enhance drug penetration, such as focused ultrasound and laser interstitial thermal therapy. Future directions include combination therapy, neoadjuvant and window-of-opportunity approaches, and adaptive platform and basket trials for clinical trial design. New GBM treatments should account for the BBB and immunosuppression by improving drug delivery, combining treatments, and integrating novel clinical trial designs. Current standard treatment for GBM includes surgery, radiotherapy, and chemotherapy. However, these treatments often fail to provide long-term tumor control. GBM is immunosuppressive, leading to local and systemic immune suppression. Immunotherapies have shown limited success in GBM due to the tumor's immunosuppressive environment. Novel therapeutics include oncolytic viruses, CAR T cells, and vaccines. The BBB restricts drug penetration, limiting therapeutic effectiveness. Strategies to overcome this include BBB-penetrant drugs, nanoparticles, antibody–drug conjugates, and radioimmunotherapy. Novel drug delivery methods such as intra-arterial delivery, convection-enhanced delivery, and laser interstitial thermal therapy are being explored. Focused ultrasound can disrupt the BBB to enhance drug delivery. Clinical trials are needed to evaluate these approaches, with a focus on combination therapies and adaptive trial designs.