We have investigated the use of ultrasound-based imaging to develop a non-invasive, safe and real-time method of guidance and monitoring for HIFU therapy. HIFU application was synchronized with the imaging frame rate to allow interference-free visualization of the region of interest. The regions treated with HIFU at intensities above the cavitation threshold appear immediately (within 30–60 ms) as hyperechoic structures in ultrasound images, confirmed to be due to microbubble activity at the focus. This HIFU dose is shown to produce minimal tissue damage, in the form of capillary rupture in an area of approximately 0.5 mm around the focus. The appearance of hyperechoic regions is potentially useful for pre-treatment targeting to ensure that the focus is located at the correct spot. The hyperechoic structures persist for 1–2 min, while the microbubbles still remain at the focus, before being absorbed. Microbubbles at the focus also provide a shield for HIFU, to prevent thermal damage of the healthy tissues located post-focally. Challenges of ultrasound-image-guided HIFU are in monitoring the tissue thermal behavior in and around the focus, and follow-up monitoring of tissues treated with HIFU. Ultrasound imaging is developing into a promising method for guidance of HIFU therapy. [Work funded by DoD, NIH.]