When studied in isolation, stimulating muscle afferents clearly increases ventilation and sympathetic vasoconstriction – but their contribution remains uncertain when activated in a physiologic setting, i.e. in the presence of other powerful influences from central command and other reflex receptors. We and others have studied exercising canines and humans to determine that metaboreflexs from the diaphragm and expiratory muscles are activated in heavy exercise in health and during moderate exercise in disease states, thereby enhancing sympathetic vasoconstrictor outflow and affecting blood flow distribution between limb and respiratory muscles. These influences on oxygen transport exacerbate the rate of exercise-induced locomotor muscle fatigue and reduce exercise performance. A unique vasoreactivity of the diaphragm vasculature contributes importantly to these selective responses. Blockade of opiate-sensitive spinal afferents from the legs all cycling intensities caused hypoventilation and reduced MAP and heart rate. Endurance exercise performance was also impaired primarily because of reduced O2 transport. On the other hand, loss of feedback via afferents from fatiguing limbs also meant less inhibition of central locomotor command, resulting in a “choice” to continue exercise (or augment power output), thereby precipitating excessive peripheral fatigue. The relative importance of muscle afferents is likely altered in the presence of CHF and COPD, with aging, in hypoxic environments and with training. Our understanding of exactly which stimuli / conditions during rhythmic exercise activates these metaboreceptors remains incomplete, as does our knowledge of additional influences arising from interactive effects between feedback and feedforward mechanisms.