The delivery of macromolecules into the central nervous system (CNS) via the blood stream is seriously limited by the blood-brain barrier (BBB). Noninvasive, transient, and local image-guided blood-brain barrier disruption (BBBD) can be accomplished using focused ultrasound exposure with intravascular injection of pre-formed microbubbles. A detailed description of the method for MRI-guided focal BBBD in animals will be described in this chapter. The method may open a new era in CNS macromolecular drug delivery.