Chronic obstructive pulmonary disease (COPD) is a smoking-related disorder that is a leading cause of death worldwide. It is associated with an accelerated rate of age-related decline in lung function due to the occurrence of destructive pathological changes such as emphysema, small airway remodeling, and mucus hypersecretion. Smokers are exposed to trillions of radicals and thousands of reactive chemicals and particles with every cigarette, thus oxidant stress is believed to be a central factor in the pathogenesis of COPD. The molecular activities of radicals, reactive oxygen, and nitrogen species can, over time, lead to a number of the detrimental changes in the lung. For instance, smoke can directly damage the mitochondrion, an organelle that has long been linked to age-related diseases associated with oxidant stress. Mitochondria are involved in a number of important cellular processes and are the largest source of endogenous reactive oxygen species (ROS) in the cell; therefore, any impairment of mitochondrial function can lead to greater oxidant damage, cellular dysfunction, and eventually to disease. Only a subset of smokers (15-50%) develops COPD, suggesting that there are polygenetic and/or environmental susceptibility factors involved in this complex disease. Here, we propose that the aerobic capacity for an individual may determine whether one is susceptible to developing COPD. Aerobic capacity is a polygenetic trait closely associated with mitochondrial function, and we suggest antioxidant defenses. Thus, those smokers who have the greatest aerobic capacity will be most resistant to the effects of chronic cigarette smoke exposure and be less likely to develop COPD.