Breathing is a spontaneous, rhythmic motor behavior critical for maintaining O₂, CO₂, and pH homeostasis. In mammals, it is generated by a neuronal network in the lower brainstem, the respiratory rhythm generator (Feldman et al., 2003). A century-old tenet in respiratory physiology posits that the respiratory chemoreflex, the stimulation of breathing by an increase in partial pressure of CO₂in the blood, is indispensable for rhythmic breathing. Here we have revisited this postulate with the help of mouse genetics. We have engineered a conditional mouse mutant in which the toxicPHOX2B^27Alamutation that causes congenital central hypoventilation syndrome in man is targeted to the retrotrapezoid nucleus, a site essential for central chemosensitivity. The mutants lack a retrotrapezoid nucleus and their breathing is not stimulated by elevated CO₂at least up to postnatal day 9 and they barely respond as juveniles, but nevertheless survive, breathe normally beyond the first days after birth, and maintain blood PCO₂within the normal range. Input from peripheral chemoreceptors that sense PO₂in the blood appears to compensate for the missing CO₂response since silencing them by high O₂abolishes rhythmic breathing. CO₂chemosensitivity partially recovered in adulthood. Hence, during the early life of rodents, the excitatory input normally afforded by elevated CO₂is dispensable for life-sustaining breathing and maintaining CO₂homeostasis in the blood.