The healthy respiratory system has a remarkable capacity for meeting the metabolic demands placed upon it during strenuous exercise. For example, in order to regulate alveolar partial pressure of oxygen and carbon dioxide during heavy workloads, a 20-fold increase in alveolar ventilation can occur. The high metabolic costs and subsequent increased work of breathing associated with this ventilatory increase can result in a number of limitations to the healthy respiratory system. Two examples of respiratory system limitations that are associated with a high work of breathing are expiratory flow limitation and exercise-induced diaphragmatic fatigue. Expiratory flow limitation can lead to an inability to increase alveolar ventilation (V (A)) in the face of increasing metabolic demands, resulting in gas exchange impairment and diminished endurance exercise performance. Furthermore, the high ventilatory requirements of endurance athletes and the inherent anatomical differences in females could make these groups more susceptible to expiratory flow limitation. Fatigue of the diaphragm has also been documented after strenuous exercise and may be related to a mechanism which increases sympathetic vasoconstrictor outflow and reduces limb blood flow during prolonged exercise. This competition between the muscles of respiration and locomotion for a limited cardiac output may have dramatic consequences for exercise performance. This brief review summarizes the literature as it pertains to the work of breathing, expiratory flow limitation, and exercise-induced diaphragmatic fatigue in healthy humans.