Compelling clinical and experimental evidence clearly indicates that tumor hypoxia remains a challenge for radiation and chemotherapy. The general consensus is that tumor hypoxia is a major cause of treatment failures. We therefore hypothesize that it would be beneficial to detect the hypoxic areas in tumors and irreversibly ablate them to reduce hypoxia related resistance. To test this hypothesis, we propose preclinical studies using a mouse tumor model and PET/MRI guidance to thermally ablate hypoxic-tissue prior to ionizing radiation. In humans, this approach may significantly shorten focused ultrasound thermal ablation treatment times since only hypoxic regions of tumors are targeted.