Reactive oxygen species, including free radicals, are produced through a number of biochemical reactions, often as a consequence of aerobic metabolism. A system of antioxidant enzymes and scavenger substrates provides protection of membrane lipids, proteins, and DNA. An imbalance between production of reactive oxygen species and antioxidant protection results in "oxidative stress." Oxidative stress is believed to contribute to numerous pathological conditions including atherosclerosis, obstructive lung disease, aging, and fatigue of skeletal muscles including the diaphragm. Strenuous exercise, inflammation, infection, obstructive lung diseases, etc. increase exposure of the diaphragm to reactive oxygen species. Emerging data indicate that reactive oxygen species alter diaphragm contractions primarily in response to low-frequency stimulation. The response of the diaphragm is profoundly influenced by the degree of oxidative stress, fatigue state, glutathione status, and age. Exercise training results in an upregulation of antioxidant enzyme activities in the diaphragm and thus could provide additional protection against oxidative stress.