The development of new chemotherapeutic agents and concepts of radiation therapy has led to new perspectives in cancer therapy. Recently developed novel agents interfere with molecular mechanisms that are altered in cancer cells. Cyclooxygenase-2 (COX-2) is an enzyme induced by a variety of factors including tumor promoters, cytokines, growth factors and hypoxia. It is involved in the metabolic conversion of arachidonic acid to prostanoids, primarily in inflammatory states and tumors. In normal tissues, prostanoids are synthesized by COX-1, and they exert numerous homeostatic physiological functions. COX-2 overexpression is linked to carcinogenesis, maintenance of progressive tumor growth and metastatic spread. COX-2 and its products may act as protectors against cell damage by ionizing radiation. In this context, the treatment with selective COX-2 inhibitors became of interest for radiation oncology within the last years. In this review we focus on the effects of COX-2 in the modulation of the radiation response and the potential clinical application as cancer preventive drug or as novel agents in adjuvant clinical settings. The experimental data available suggest that COX-2 inhibitors can enhance the radiation response in tumors without serious side effects to the normal tissue. In conclusion COX-2 might be a useful tool for cancer prevention and represents a potential molecular target for improving cancer treatment in combination with radiotherapy.