Chronic obstructive pulmonary disease is a leading cause of morbidity and mortality, which is most commonly associated with smoking or exposure to environmental pollutants. Unfortunately, there is an inadequate understanding of the molecular and physiological determinants governing one's susceptibility for developing COPD. Here, we describe a novel hypothesis: Individuals with intrinsically low aerobic exercise capacity are more likely to develop COPD after exposure to key risk factors. The hypothesis is based on observations that aerobic exercise capacity is tightly associated with mortality across many complex diseases. The premise is supported by recent studies demonstrating that smokers who exercise regularly are less likely to develop or be hospitalized for COPD. Herein, we describe the evolutionary and molecular basis for this hypothesis and how it is a natural extension of previous theories explaining COPD susceptibility.