Recent guidelines define chronic obstructive pulmonary disease (COPD) as a preventable and treatable disease characterized by airflow limitation and systemic consequences. Airflow limitation in COPD worsens over years as assessed by the forced expiratory volume in one second (FEV1). Regardless, while it is likely that cardiovascular and other systemic components also worsen as COPD progresses, there are no accepted or validated outcomes to measure such pathophysiologic changes as they relate to COPD disease progression. It is clear that health status in COPD is more closely related to levels of patients' physical functional capacity than it is to changes in FEV1. Furthermore, the relative contributions of pathoanatomic changes such as small airways fibrosis and pulmonary emphysema to declining airflow remain unknown. These features may even progress at different rates in the same individuals. Although stopping smoking is the only intervention shown to alter the relentless progression of COPD, the resultant slowing of FEV1 decline takes several years to evince and requires at least 1,000 subjects to demonstrate annual therapeutic benefits of as little as 20 ml. The FEV1 cannot distinguish between peribronchiolar fibrosis and emphysema and it is feasible that, as techniques are developed and validated, lung imaging methodologies may become important and sensitive outcomes measures of time- and age-dependent lung structural changes in COPD. The development of biomarkers of lung damage, pulmonary inflammation, and systemic disease will be essential to our further understanding of the natural history of COPD and the discovery of new, effective treatments for its progression.