Tumor hypoxia is a major constraint for the tumor treatment by radiotherapy. The efficacy of ionizing radiation directly relies on adequate oxygen tensions. Furthermore, hypoxia is related to malignant progression, increased invasion, angiogenesis and an increased risk of metastases formation. Two different types of strategies can be used to overcome the problem of hypoxia-mediated radioresistance. The first strategy encompasses a variety of different methods to improve the tumor oxygenation during radiotherapy. The second strategy tries to target hypoxia as a relatively unique feature of tumor tissue by means of drugs, which are activated under hypoxic conditions and act as hypoxic radiosensitizers or hypoxic cytotoxins. This article reviews in brief the clinical experience with different generations of hypoxic radiosensitizers and hypoxic cytotoxins, which have been applied in combination with primary radiotherapy during the last three decades.