The dynamics of infection in chronic obstructive pulmonary disease (COPD) are complex, and microbiome technology has provided us with a new research tool for its better understanding. There is compartmentalization of the microbiota in the various parts of the lung. Studies of the lower airway lumen microbiota in COPD have yielded confusing results, and additional studies with scrupulous attention to prevent and account for upper airway contamination of bronchoalveolar lavage samples are required. Lung tissue microbiota has been examined in three studies, which also demonstrate varied results based on the site of sampling (bronchial mucosa, lung parenchyma), and this variation extends to sampling sites within a lobe of the lung. The Vicious Circle Hypothesis embodies how an altered lung microbiome could contribute to COPD progression. Relating microbiota composition to airway and systemic inflammation and clinical outcomes are important research questions. Although various obstacles need to be surmounted, ultimately lung microbiome studies will provide new insights into how infection contributes to COPD.