Glioblastomas are rare tumors but aggressive and often incurable. Since clinical trial enrollment is limited by the relative rarity of the disease, clinical trials should be well designed so that advances are made efficiently. The field has been dominated by smaller Phase II studies since they provide the initial screening of drug efficacy. These studies are prone to issues of selection bias, inappropriate historic controls and confounding clinical variables. There are also issues specific to glioblastoma, including the difficulty in interpreting radiographic responses in the setting of treatment effects and agents that affect vascular permeability and the difficulty of performing pharmacokinetic and pharmacodynamic studies given the relative inaccessibility of the CNS compartment. These barriers have also hindered the development of radiographic and molecular biomarkers. As we move into the era of personalized medicine, it is increasingly important to address these issues in the design of clinical trials.