We hypothesize that focused ultrasound can be used – under MRI guidance - to delineate cancers as well as other pathologies with a precise pattern of small ablation marks that precisely show the position and boundaries of tumors. These tattoos can be designed to be highly conspicuous visually, using optical sensors, and/or on CT or Ultrasound. In the present application we focus on optimizing the conspicuity of the lesions on cone-beam CT scans, in order to guide radiotherapy. This pattern of ‘tattoos’ can be encoded very rapidly because the total volume of the ‘tattoos’ will be very small. Conspicuity of the ‘tattoos’ will be maximized by developing a heating protocol that first produces hemorrhage with mild heating, and subsequently increases heating to ‘fix’ the hemorrhaged blood in the tissue. Conspicuity of the ‘tattoos’ will be further increased by using focused ultrasound to trap a variety of contrast agents. The tattoos can be used to guide surgery, radiotherapy, biopsies and other interventional procedures. Use of HIFU to produce the tattoos will be clinically acceptable, since the tattoos will cause far less tissue damage than the subsequent therapy they are designed to guide, and the tattoos can be very rapidly encoded. In fact, by guiding the therapeutic intervention more accurately, the tattoos can reduce damage caused by therapy in normal tissue. In this application we develop and test the use of ‘HIFU tattoos’ to guide radiation therapy of cancer in a pre-clinical rabbit cancer model.