Heavy whole-body exercise, requiring a 10- to 15-fold increase in minute ventilation, encroaches on the capacities of the respiratory muscle system to respond. Recently, using the technique of bilateral phrenic nerve stimulation, it has been shown that heavy endurance exercise (>85% of˙VO2max) lasting >8-10 min causes diaphragmatic fatigue (15-30% reduction in transdiaphragmatic pressures when electrically stimulated at low frequencies [1-20 Hz] supramaximally). The fatigue appears to be due to an interaction of diaphragmatic work (i.e., pressure production) combined with effects related to exercise intensity (i.e., increased blood flow competition with the locomotor muscles and increased production of metabolic by-products) and requires >60 min for recovery. Fitness (i.e., as implied from˙VO2max) appears to allow greater diaphragmatic work for a similar degree of fatigue. Unloading the respiratory muscles (with helium/oxygen gas or using a pressure-assist device) during heavy exercise <90-95% of˙VO2max does not appear to alter exercise time, ˙VO2max, or minute ventilation, implying that respiratory muscle fatigue plays little role in altering human performance at these work intensities. However, unloading the respiratory system with helium at work intensities >90-95% of˙VO2max has been shown to improve exercise time. This would imply that respiratory muscle fatigue may play a role in limiting human performance at the extremes of human performance or that other factors related to the respiratory system (i.e., alterations in the sensation of dyspnea or mechanical load) may play an important role.