Chronic obstructive pulmonary disease (COPD) causes significant morbidity and mortality and represents the fourth leading cause of death in the world. Roflumilast is the first oral phosphodiesterase inhibitor indicated to reduce the risk of COPD exacerbations in patients with severe COPD associated with chronic bronchitis and history of exacerbations. Roflumilast and its active metabolite have been associated with increased cyclic adenosine monophosphate (cyclic AMP) in the lungs and positive responses with inflammatory markers. Significant improvements in forced expiratory volume (1 sec) have been observed in clinical trials comparing roflumilast with placebo. Combination therapy of roflumilast (500 μg) with long-acting beta agonists resulted in reduced COPD exacerbations in patients with severe COPD. Adverse effects include weight loss, diarrhea, nausea, and psychiatric disturbances. Roflumilast may be associated with significant drug-drug interactions with CYP3A4 inducers (strong) and immunosuppressants. Roflumilast is a promising new agent in the treatment of COPD; however, additional studies comparing roflumilast with inhaled corticosteroids plus long-acting bronchodilators are needed.