Focused ultrasound with microbubbles promises unprecedented advantages for blood-brain barrier disruption over existing intracranial drug delivery methods, as well as a significant number of tunable parameters that affect its safety and efficacy. This review provides an engineering perspective on the state-of-the-art of the technology, considering the mechanism of action, effects of microbubble properties, ultrasound parameters and physiological variables, as well as safety and potential therapeutic applications. Emphasis is placed on the use of unified parameters, such as microbubble volume dose (MVD) and ultrasound mechanical index, to optimize the procedure and establish safety limits. It is concluded that, while efficacy has been demonstrated in several animal models with a wide range of payloads, acceptable measures of safety should be adopted to accelerate collaboration and improve understanding and clinical relevance.