Cyclooxygenase-2 (COX-2) overexpression is seen in many malignancies including lung cancer. In non-small cell lung cancer (NSCLC), COX-2 is overexpressed in most adenocarcinomas and squamous cell carcinomas. Elevated tumor COX-2 prostaglandin E(2) (PGE(2)) levels have been implicated in angiogenesis, tumor invasion, resistance to apoptosis, and suppression of antitumor immunity. Preclinical animal model studies show tumor reduction when animals are treated with either nonspecific or specific inhibitors of COX-2. These studies suggest nonsteroidal anti-inflammatory drugs may act on multiple tumor-progression targets via both COX-2-dependent and-independent pathways. Consistent with these findings, epidemiologic evidence has shown a decreased incidence of lung cancer in patients who use nonsteroidal anti-inflammatory drugs. Based on these observations, celecoxib, a selective COX-2 inhibitor, has been evaluated in combination with chemotherapy for the management of metastatic NSCLC in patients who have failed prior chemotherapy. Several clinical trials are ongoing that evaluate celecoxib in combination with chemoradiation for unresectable, locally advanced NSCLC. Another trial evaluating celecoxib in a preoperative combination with paclitaxel and carboplatin has generated overall clinical response rates at least comparable to those reported in the Bimodality Lung Oncology Team trial. Ongoing clinical trials are also evaluating the combination of celecoxib with chemotherapy and/or radiation or celecoxib in combination with epidermal growth factor receptor inhibitors of NSCLC. This article reviews preclinical information on COX-2 inhibitors in lung cancer and presents updated data from several ongoing clinical trials that are evaluating celecoxib in NSCLC.