The importance of respiratory muscle fatigue, particularly of the diaphragm, has become well recognized in the last decade. If the diaphragm muscle fails, so does effective ventilation and tissue respiration. Balance between energy supply and demand determines diaphragmatic endurance. An imbalance between energy supply and demand leads to the development of diaphragmatic fatigue. It has become clear that the process of fatigue is a complex phenomenon with multiple mechanisms accounting for changes in muscle performance. The various mechanisms involved are probably interdependent, synergistic, and integrative in nature. This article focuses on the concept of diaphragm fatigue and explores the mechanisms occurring with diaphragm fatigue including sodium-potassium derangements, which cause a decrease in velocity of propagation of muscle action; inhibition of calcium release from the sacroplasmic reticulum; and increased oxygen free radical formation related to cellular energetics. Additionally, review of therapeutic approaches to the treatment of diaphragm fatigue are presented.