The response of 96 slowly adapting airway stretch receptors (SARs) to inhaled CO2 was studied in 26 puppies, which were anesthetized, paralyzed, and passively ventilated with the chest open. Both inhibitory and excitatory influences were obtained during CO2 inhalation depending on the presence or absence of a partially intact parasympathetic innervation and the receptor location. In puppies in the vagotomized condition, tracheal SARs of the youngest puppies (1–10 days) were inhibited (68% of control discharge), whereas bronchial SARs were unaffected by CO2. In the older age groups (12–17 and 26–30 days) there was a gradual acquisition of the adult response with a progressive increase in the inhibitory action of CO2 on bronchial SARs, whereas tracheal SARs became less affected. An excitatory action of CO2 could be found if the contralateral vagus nerve was intact. This response, which was abolished by vagotomy or atropine, was limited to tracheal SARs (occurring in 8 out of 23 receptors with the remainder inhibited) and was not accompanied by changes in transpulmonary pressure. Considering that only one-half of the functional efferent innervation of the trachea was present (i.e., left vagus only) and that the response has never been reported in the adult, the stimulation of SAR activity via smooth muscle contraction may represent a mechanism that could severely limit the neonate's ability to respond to periods of apnea or asphyxia.