Supplemental long-term oxygen therapy (LTOT) is a well-established therapy that improves mortality in patients with chronic obstructive pulmonary disease (COPD) with resting hypoxemia. In the large number of patients with COPD who do not have severe resting hypoxemia but who desaturate with exercise, the clinical benefits that can be obtained by supplemental O₂ therapy during exercise is an area of interest and active research. A summary of current evidence for benefits of supplemental O₂ therapy and a review of physiologic mechanisms underlying published observations are reviewed in this article.