Chronic obstructive pulmonary disease (COPD) is a common disorder with symptoms of chronic cough and progressive dyspnea caused by chronic bronchitis or emphysema. Acute exacerbations of COPD contribute to the accelerated decline in lung function characteristic of this disease and are associated with significant cost, morbidity, and mortality for patients. Controversy exists as to whether exacerbations are caused primarily by inflammation, infection, or perhaps a combination of both conditions. Advances in the pathogenesis of COPD have shed light on the role of inflammation in this condition and highlighted the differences in the inflammatory response present in COPD compared with asthma. Infectious agents often are suspected as causing acute exacerbations of COPD, and antibiotics are frequently prescribed empirically to patients. We review the evidence for an inflammatory and infectious etiology for exacerbations of COPD and compare and contrast how each impacts on this disease.