Invasive open surgery used to be compulsory to access tumor mass to perform excision or resection. Development of minimally invasive laparoscopic procedures followed, as well as catheter-based approaches, such as stenting, endovascular surgery, chemoembolization, brachytherapy, which minimize side effects and reduce the risks to patients. Completely noninvasive procedures bring further benefits in terms of reducing risk, procedure time, recovery time, potential of infection, or other side effects. Focusing ultrasound waves from the outside of the body specifically at the disease site has proven to be a safe noninvasive approach to localized ablative hyperthermia, mechanical ablation, and targeted drug delivery. Focused ultrasound as a medical intervention was proposed decades ago, but it only became feasible to plan, guide, monitor, and control the treatment procedures with advanced radiological imaging capabilities. The purpose of this review is to describe the imaging capabilities and approaches to perform these tasks, with the emphasis on magnetic resonance imaging and ultrasound. Some procedures already are in clinical practice, with more at the clinical trial stage. Imaging is fully integrated in the workflow and includes the following: (1) planning, with definition of the target regions and adjacent organs at risk; (2) real-time treatment monitoring via thermometry imaging, cavitation feedback, and motion control, to assure targeting and safety to adjacent normal tissues; and (3) evaluation of treatment efficacy, via assessment of ablation and physiological parameters, such as blood supply. This review also focuses on sonosensitive microparticles and nanoparticles, such as microbubbles injected in the bloodstream. They enable ultrasound energy deposition down to the microvascular level, induce vascular inflammation and shutdown, accelerate clot dissolution, and perform targeted drug delivery interventions, including focal gene delivery. Especially exciting is the ability to perform noninvasive drug delivery via opening of the blood-brain barrier at the desired areas within the brain. Overall, focused ultrasound under image guidance is rapidly developing, to become a choice noninvasive interventional radiology tool to treat disease and cure patients.