This two-part study sought to determine the relationship between arterial PCO2, CO2 chemoresponsiveness, and ventilation during exercise in healthy children and children with cystic fibrosis (CF). In the first part, we measured the hypercapnic ventilatory response (HCVR) in 16 healthy children and 16 patients with CF, and compared HCVR with the ventilatory response to progressive exercise (ΔV̇E/ΔV̇CO2). In the second part, we assessed the relation between age, the ventilatory equivalent for CO2 (V̇E/V̇CO2), and arterialized capillary PCO2 (PaCO2), during exercise in 28 healthy children and 23 children with CF. The HCVR showed an age-related decline in both healthy controls and CF subjects. In addition, there was a correlation between forced expiratory flow from 25 to 75% of forced vital capacity and the HCVR, regardless, of age. In controls, but not in CF, there was also a decline in ΔV̇E/ΔV̇CO2 with increasing age; and there was a significant correlation between ΔV̇E/ΔV̇CO2 and HCVR. Findings in the second part were similar, with a significant inverse correlation between age and V̇E/V̇CO2) during steady state exercise only in healthy controls. However, when physiologic dead space was taken into account, both CF and healthy control children showed a significant decline in V̇A/V̇CO2 with age. When all subjects were grouped together, there was a statistically significant correlation between PaCO2 and age, such that younger subjects had lower PaCO2 than older subjects. Age and PaCO2 together accounted for 71% of the variance in V̇A/V̇CO2. We conclude that younger children ventilate proportionately more on exercise than older children because they regulate PaCO2 about a lower set point. As the ventilatory response to exercise is significantly correlated with the HCVR, and the latter can be reduced in the presence of airways obstruction, an innately low HCVR could permit the development of exertional hypercapnia in some CF patients with advancing pulmonary disease.