High intensity focused ultrasound (HIFU) is a rapidly developing medical technology that relies on the focusing of acoustic waves to treat remote tissue sites inside the body without damaging intervening tissues. HIFU can be used to treat benign and malignant tumors, dissolve blood clots, enhance drug delivery to specific sites, and even to ablate brain tissue causing essential tremors. A key feature of HIFU is the ability to maintain a very thin margin between treated and untreated tissue. However, the position and extent of treatment can be sensitive to many factors, including blood perfusion, tissue properties, and nonlinear acoustic propagation. In order to ensure effective treatments and to avoid adverse effects from unintended tissue injury, it is necessary to accurately determine the 3D acoustic field that will be delivered to the patient. While standard practices for characterizin diagnostic ultrasound are well established, the lack of analogous metrology techniques for therapeutic ultrasound remains an impediment to broader clinical acceptance of HIFU. To predict 3D HIFU fields in tissue, it is constructive to consider two components: vibratory performance of the source and acoustic propagation to the treatment site. Typically, hydrophone measurements of pressures in water are made to characterize the source; next, these measurements are derated to account for propagation in tissue rather than water. However, such an approach can produce incomplete or erroneous results because collecting hydrophone measurements throughout a 3D volume is often impractical, hydrophone measurements at the high-pressure focus are flawed, and derating schemes fail to account for nonlinear propagation effects. A more complete approach can address these shortcomings by combining acoustic holography for source characterization and modeling of nonlinear propagation in tissue. Acoustic holography involves measuring both pressure magnitude and phase over a 2D surface. By including phase data, holography provides detailed, quantitative information about a source's vibrations, which can be used as boundary conditions for modeling the full 3D field. Though recognized as valuable, acoustic holography remains difficult to implement; accordingly, this proposal is designed to advance holography as a metrology tool for therapeutic ultrasound. In Aim 1, practical aspects of data collection will be improved and standardized for characterizing sources operating in continuous-wave regimes at low powers. Aim 2 will extend the approach to sources operating in pulsed regimes. In Aim 3, nonlinear holography will be developed to characterize directly how sources vibrate at high power levels. By improving the practical implementation of holography and extending its use to include clinical operating conditions, this effort will demonstrate a comprehensive metrology approach for HIFU sources that can be used by manufacturers and practitioners. This work will benefit public health by facilitating the development of regulatory guidelines, FDA approvals of new HIFU therapies, safer and more effective devices, and controlled clinical dosing.