Glioblastoma (GBM) remains resistant to most conventional treatments, with a 5-year overall survival rate of only 6.8%. The blood–brain barrier (BBB) and tumor microenvironment pose significant challenges for effective therapy development. This review discusses novel approaches to improve drug delivery across the BBB, including nanoparticle formulations, antibody-drug conjugates, convection-enhanced delivery, and intra-arterial delivery. It also explores methods to enhance drug penetration, such as focused ultrasound and laser interstitial thermal therapy. Future opportunities include combination therapies, neoadjuvant and window-of-opportunity approaches, and adaptive platform and basket trials to optimize clinical trial design. The review highlights the need for improved drug delivery strategies and innovative clinical trial designs to overcome the limitations of current treatments for GBM.Glioblastoma (GBM) remains resistant to most conventional treatments, with a 5-year overall survival rate of only 6.8%. The blood–brain barrier (BBB) and tumor microenvironment pose significant challenges for effective therapy development. This review discusses novel approaches to improve drug delivery across the BBB, including nanoparticle formulations, antibody-drug conjugates, convection-enhanced delivery, and intra-arterial delivery. It also explores methods to enhance drug penetration, such as focused ultrasound and laser interstitial thermal therapy. Future opportunities include combination therapies, neoadjuvant and window-of-opportunity approaches, and adaptive platform and basket trials to optimize clinical trial design. The review highlights the need for improved drug delivery strategies and innovative clinical trial designs to overcome the limitations of current treatments for GBM.