This chapter reviews the physiology of the blood–brain barrier (BBB) and its disruption to optimize drug delivery. Effective penetration of the BBB has been a significant hurdle in treating neurological diseases, particularly in treating brain tumors. This chapter describes the anatomy and physiology of the BBB, elucidating the roles of its different components that maintain its integrity. It reviews the current and future methods of penetrating the BBB. Intra-arterial osmotic disruption and focused ultrasound with microbubbles are two of the most clinically relevant methods. This chapter describes how disruption of the BBB can be monitored to optimize barrier disruption and minimize the risk of injury. It enumerates the known complications and adverse effects of BBB disruption. It concludes by describing the emerging methods for delivering drugs and how the field can advance in the future.