Summary The blood-brain barrier prevents most drugs from reaching the central nervous system and is one of the biggest problems in developing new effective therapies for patients with brain tumors, neurodegenerative diseases, and other disorders. The use of ultrasound in combination with injected microbubble agents has emerged as a prom- ising method to temporarily disrupt the barrier. After over a decade of preclinical studies in animals, multiple commercial systems have been developed and clinical trials have begun. Early experience with these trials have shown several problems that were predicted by the preclinical work. The clinical treatments use lower doses of microbubbles, have to overcome the variable attenuation of the human skull, and are often in white matter. As a result, treatments have been suboptimal. The purpose of this proposal is to provide a roadmap to clinical success for ultrasound-mediated blood-brain barrier opening. We will develop new treatment planning methods that ac- count for the human skull, electronic steering of the focused ultrasound beam, and variations in microbubble concentrations in different tissue structures. These methods will be employed to improve safety and control of the procedure. Next, we will investigate whether we can improve our ability to control the procedure in white matter targets and evaluate the safety of repeated blood-brain barrier disruption in white matter targets. Finally, using what we have learned, we will investigate whether we can deliver sufficient drugs to treat a highly infiltrating tumor model. If successful, this work could have a significant impact on future use of this exciting technology.