Ventilatory and cardiovascular responses to exercise are primarily regulated by two largely separate systems. The first, a feed-forward mechanism termed ‘central command’, elicits cardiovascular and ventilatory responses to exercise. The second, a feedback mechanism, reflexly changes ventilation and circulation as a consequence of limb muscle contraction. The focus here is on the latter. Numerous animal and human studies have suggested a key role for muscle afferents in evoking cardiovascular and ventilatory responses during exercise. Specifically, non-nociceptive Group III/IV muscle afferents, the so-called ‘ergoreceptors’, are thought to depict the afferent arm of the cardiovascular and ventilatory reflexes, which are mediated via neural circuits in the nucleus tractus solitarius and the ventrolateral medulla. Recent human studies using local anaesthetics (lumbar epidural space) to block the central projection of Group III/IV muscle afferents during whole-body endurance exercise (leg cycling) found attenuated, similar or even increased cardiovascular and ventilatory responses when the identical exercise was performed with blocked muscle afferents. Although some of these studies conform to the idea that continuous afferent feedback is necessary for adequate ventilatory and circulatory responses, others are contradictory, leaving the exact role of muscle afferents in the cardioventilatory control during endurance exercise controversial. At least some of these conflicting findings may be explained by the use of local anaesthetics, which attenuate efferent as well as afferent nerve activity. The effects of local anaesthetics on efferent nerves cause a drug-induced ‘muscle weakening’, which inevitably requires an increase in central command in order to work at and/or maintain a given external workload. More recent studies designed to circumvent the confounding impact of local epidural anaesthetics now provide valuable insights into the effects of muscle afferents on the circulatory and ventilatory response to whole-body endurance exercise. By using lumbar intrathecal fentanyl, a selective µ-opioid receptor agonist, we were able to inhibit the central projection of Group III/IV muscle afferents without affecting the muscle’s force-generating capacity and therefore without affecting central command during the exercise. The outcome of these studies clearly shows that when Group III/IV muscle afferents from the lower limbs are blocked during endurance exercise of various intensities, ranging from mild to heavy, circulation and pulmonary ventilation are substantially compromised. This not only causes arterial hypoxaemia and attenuates both perfusion pressure and blood flow, which eventually reduces O2 delivery to the working muscles, but also facilitates ventilatory and metabolic acidosis, all of which combine to accelerate the development of peripheral locomotor muscle fatigue during exercise. These findings suggest that continuous sensory feedback from working skeletal muscle may depict a vital component in providing a high capacity for rhythmic endurance exercise because controlled muscle perfusion and O2 delivery determine the fatigability of skeletal muscle and thus affect its performance.