Ventilation increases during prolonged heavy exercise in humans (1), but the impact of dehydration and hyperthermia on pulmonary ventilation and gas exchange remains unclear. In a series of human studies, we sought to: 1) characterise the influence of dehydration and hyperthermia, and the associated blunted pulmonary and systemic circulation, on the ventilatory and pulmonary gas exchange responses to endurance exercise; 2) isolate the contribution of dehydration and hyperthermia on the observed hyperventilation; and 3) discern the influence of sympatho-adrenergic activity in the ventilatory response to prolonged exercise.  Methods: Following ethical approval, twenty-nine endurance‐trained males took part in four studies. In study 1, on separate days, seven participants performed two submaximal exercises in the heat at a constant workrate initially eliciting 61±2% V̇O2max. On the first day, they cycled until volitional exhaustion (135±11 min), while developing progressive dehydration and hyperthermia (DE-HY; 3.9±0.7% body mass loss and oesophageal temperature (Toes) 39.7±0.6°C). On the second day (control), they cycled for the same duration maintaining euhydration and stabilising Toes at 38.2±0.3°C. In studies 2 and 3, different participants (n=7-8) completed a series of submaximal cycling bouts that induced a state of either isolated hyperthermia, isolated dehydration, combined dehydration and hyperthermia, or euhydration (control). In study 4, while cycling for 120 min at a constant workrate initially eliciting 65% V̇O2max, seven participants were intravenously infused, from 30 min onward, with equal volumes of either an adrenaline solution (0.1 µg·kg-1·min-1) or a saline solution (control). Ventilatory responses, pulmonary inspiratory and expiratory gases, V̇O2 and carbon dioxide output (V̇CO2) were measured in all the studies. Arterial blood gases were obtained in study 1. Statistical significance was determined using repeated measures ANOVA. Results: In study 1, at rest and after 20 min of exercise, ventilation (V̇E), blood gases, V̇CO2 and V̇O2 were similar in both trials (all P>0.05). Thereafter, V̇E increased 19±8 l·min-1 in DE-HY, but 6±2 l·min-1 in control (both P≤0.006). Thus, at exhaustion, V̇E was 13±8 l·min−1 higher in DE-HY. Hyperventilation in DE-HY was accompanied by a lower PaCO2 (4±3 mmHg) and higher respiratory frequency (7±4 beaths·min-1), arterial partial pressure of O2 (11±6 mmHg), and mixed-venous arterial CO2 and O2 content differences (23±11 ml·l-1 and 32±7 ml·l-1, respectively) (all P≤0.006). Despite a lower cardiac output in DE-HY (3.3±1.5 l·min-1; P=0.001), V̇O2 remained unchanged and V̇CO2 was elevated. The increased V̇E during exercise in both conditions was closely related to the rise in Toes and circulating catecholamines (Fig. 1). Hyperthermia independently increased V̇E to a similar extent as combined dehydration and hyperthermia (5.7±2.3 versus 5.0±2.2 l·min-1; P=0.886), whereas preventing hyperthermia in dehydrated individuals restored V̇E to control levels (0.8±3.5 l·min-1; P=0.719). Adrenaline infusion caused hyperthermia and increased V̇E (4.9±3.2 l·min-1; P=0.006; Fig. 1).  Conclusion: Hyperthermia is the main stimulus increasing V̇E during prolonged exercise with distinct hydration and circulation levels. Sympathoadrenal discharge is a contributing factor to hyperthermia-induced hyperventilation. Adjustments in pulmonary gas exchange during endurance exercise with dehydration and hyperthermia ameliorate metabolic and acid-base disturbances in the face of a markedly blunted pulmonary and systemic circulation.