Chronic obstructive pulmonary disease (COPD) is one of few chronic disorders with rising mortality and morbidity. It is a highly prevalent disorder, characterized by highly heterogeneous clinical symptoms, health status, and disease progression. COPD is also characterized by an inflammatory/immune response that persists despite smoking cessation and varies by the patient population, method of assessment, and timing of measurement. Bacterial colonization or infection is ubiquitous in patients with COPD and, until recently, has been predominantly assessed using culture-based methodologies. This colonization has been believed to be biologically relevant. It has been estimated that more than 70% of the bacterial species on body surfaces cannot be cultured by standard techniques. As such, advanced culture-independent techniques have been developed that target bacterial genes, such as the 16S ribosomal RNA gene, that function as molecular chronometers. Application of these techniques in patients with COPD has suggested microbial diversity that varies by age, disease severity, and medication use. All of these data provide unique and rapidly evolving insight into the potential role of the respiratory microbiome in disease genesis and expression.