Mechanisms of radioresistance at different pO2. Under the radiobiological or severe hypoxia (pO2 < 3 mmHg), the oxygen fixation hypothesis (OFH) is likely the main mechanism of radioresistance even though expression of DNA repair genes is strongly reduced. In contrast, hypoxia-activated pathways, both HIF-dependent and independent, will be actively operative under the pathological hypoxia (pO2 = 3–15 mmHg) to elicit a multitude of molecular and cellular changes. Chief among them, the cancer stem cell (CSC) phenotype has the potential to play a prominent role in conferring radioresistance.