Since cyclooxygenase-2 (COX-2) is overexpressed in malignant tissues, the COX-2 mediated signaling pathway has been recognized as potential target for therapeutic intervention. In most human tumors, COX-2 overexpression has been associated with tumor aggressiveness and poor clinical outcome. In vitro studies show inhibition of cell proliferation by selective COX-2 inhibitors alone, and enhancement of the response to irradiation. In vivo experimental reports demonstrate enhanced tumor response and impediment of tumor neovascularization following radiotherapy combined with COX-2 inhibition. Clinical studies on the combination of irradiation with COX-2 inhibitors are emerging. Taken together, the perspective for the combined approach of radiotherapy with COX-2 inhibition yields clinical significance since preclinical data demonstrate selective COX-2 inhibitors to act as radiosensitizer in tumor treatment.