Chronic obstructive pulmonary disease (COPD) exacerbations have a major impact on patients with COPD, yet they are complex events that are associated with a number of triggers and affected by the underlying disease process. A number of conditions can mimic the symptoms of an exacerbation and require evaluation. Airway and systemic inflammatory changes at exacerbation are modulated by infective factors (viruses and bacteria) and lead to the pathophysiologic effects seen at exacerbations with increase in airflow obstruction. Although bacteria or viruses can be isolated at exacerbation, often these organisms act in combination and lead to greater inflammatory changes and more severe exacerbation. Underlying structural changes such as radiologic changes of bronchiectasis that can be found in COPD can also modulate exacerbation severity and contribute to morbidity associated with exacerbations.