In the past two decades, high-intensity focused ultrasound (HIFU) in combination with diagnostic ultrasound (USgFUS) or magnetic resonance imaging (MRgFUS) opened new ways of therapeutic access to a multitude of pathologic conditions. The therapeutic potential of HIFU lies in the fact that it enables the localized deposition of high-energy doses deep within the human body without harming the surrounding tissue. The addition of diagnostic ultrasound or in particular MRI with HIFU allows for planning, control and direct monitoring of the treatment process. The clinical and preclinical applications of HIFU range from the thermal treatment of benign and malign lesions, targeted drug delivery, to the treatment of thrombi (sonothrombolysis). Especially the therapy of prostate cancer under US-guidance and the ablation of benign uterine fibroids under MRI monitoring are now therapy options available to a larger number of patients. The main challenges for an abdominal application of HIFU are posed by partial or full occlusion of the target site by bones or air filled structures (e.g. colon), as well as organ motion. In non-trivial cases, the implementation of computer based modeling, simulation and optimization is desirable. This article describes the principles of HIFU, ultrasound and MRI therapy guidance, therapy planning and simulation, and gives an overview of the current and potential future applications.