The North American Brain Tumor Consortium (NABTC) is a multi-institutional consortium with the primary objective of evaluating novel therapeutic strategies through early phase clinical trials. The NABTC has made substantial changes to the design and methodology of its trials since its inception in 1994. These changes reflect developments in technology, new types of therapies, and advances in our understanding of tumor biology and biological markers. We identify the challenges of early clinical assessment of therapeutic agents by reviewing the clinical trial effort of the NABTC and the evolution of the protocol template used to design trials. To better prioritize effort and allocation of patient resources and funding, we propose an integrated clinical trial design for the early assessment of efficacy of targeted therapies in neurooncology. This design would mandate tissue acquisition prior to therapeutic intervention with the drug, allowing prospective evaluation of its effects. It would also include a combined phase 0/I pharmacokinetic study to determine the safety and biologically optimal dose of the agent and to verify successful modulation of the target prior to initiating a larger, phase II efficacy study.