Cancer-related pain affects up to 80% of patients with malignancies. Pain is an important distressing symptom that diminishes the quality of life and negatively affects the survival of patients. Opioid analgesics are generally the primary therapy for cancer-related pain, with surgery, radiation therapy, chemotherapy, and other interventions used in cases of treatment-resistant pain. These treatments, which can be associated with substantial side effects and systemic toxicity, may not be effective. High-intensity focused ultrasound is an entirely noninvasive technique that is approved for treatment of uterine fibroids, bone metastases, and essential tremors. With magnetic resonance imaging or ultrasonographic guidance, high-intensity ultrasound waves are focused on a small well-demarcated region to result in precise localized ablation. This treatment may represent a multimodality approach to treating patients with malignant diseases-facilitating pain palliation, enhanced local drug delivery and radiation therapy effects, and stimulation of anticancer specific immune responses, and potentially facilitating local tumor control. Focused ultrasound can be used to achieve pain palliation by producing several effects, including tissue denervation, tumor mass reduction, and neuromodulation, that can influence different pathways at the origin of the pain. This technology has several key advantages compared with other analgesic therapies: It is completely noninvasive, might be used to achieve rapid pain control, can be safely repeated, and can be used in combination with chemotherapy and radiation therapy to enhance their effects. Online supplemental material is available for this article. ©RSNA, 2018.