Hypoxia is a common feature of malignant tumors. There is an interactive connection between hypoxia and chemoresistance, radioresistance, invasiveness, and angiogenesis. Therefore, tumor hypoxia has been considered as a validated target for treating cancer. This review focuses on the role of hypoxia on chemoresistance and radioresistance. In addition, we address several approaches targeting tumor hypoxia, known as hypoxia-targeted therapy.