Aromatase inhibitors (AIs) are well established in the treatment of metastatic hormone-sensitive breast cancer in postmenopausal women. Cyclooxygenase (COX)-2 inhibitors have demonstrated efficacy in reducing cancer risk in animal and human studies. In several preclinical studies, combination AI plus COX-2 inhibitor therapy has shown a synergistic antitumor effect. This review describes the utility of AI plus COX-2 inhibitor therapy and discusses the completed and ongoing clinical trials investigating treatment with the AI exemestane and the COX-2 inhibitor celecoxib in the neo-adjuvant and metastatic breast cancer settings. In general, combination therapy had comparable or better efficacy compared with AI monotherapy using the end points of progression-free survival, overall response rate, clinical benefit rate, time to progression, and duration of clinical benefit. All therapies were well tolerated. There appeared to be a beneficial impact on serum lipid levels for patients receiving combination therapy in a neo-adjuvant trial despite the known cardiovascular toxicity risk associated with COX-2 inhibitors. In conclusion, AIs plus COX-2 inhibitors have shown promising efficacy and safety for the treatment of patients with metastatic breast cancer. Careful monitoring during future trials will be necessary to accurately assess the risk-benefit ratio of combination therapy.