There has been increasing interest in the role of purines in the nervous system. In addition to its known role as an intracellular energy source, ATP also functions as an extracellular signalling molecule (acting through ionotropic P2X and metabotropic P2Y receptors) in the central and peripheral nervous system and many peripheral tissues. Immunohistochemical studies demonstrate the presence of ATP receptors throughout the brainstem. The role of ATP in central mechanisms controlling respiratory activity has been studied in our laboratories over the last 6 years. Results obtained to date suggest that ATP-mediated purinergic signalling plays an important role in several brainstem mechanisms responsible for respiratory control. (i) The role of ATP in central CO₂ chemosensory transduction. Central respiratory chemoreceptors are essential for maintenance of constant levels of arterial PCO₂, and pH. Our recent experimental data suggest that the purine nucleotide ATP acting via both ionotropic P2X and metabotropic P2Y receptors may play an important role in central chemosensory transduction. It was found that in response to an increase in PCO₂/[H+] (hypercapnia) chemosensitive structures located on the ventral surface of the medulla oblongata rapidly release ATP, which acts locally within the medullary respiratory network to evoke adaptive enhancement in breathing. (ii) The role of ATP in the hypoxic ventilatory response. Using transgenic animal models we demonstrated that in the carotid body ATP, released by the O₂-sensitive glomus cells and acting at P2X receptors located on the afferent terminals of the carotid sinus nerve, triggers enhancement of ventilation during hypoxia. P2X₂ receptors are expressed by physiologically identified respiratory neurones of the medullary ventral respiratory column. Marked ventilatory depression occurs during hypoxia in mice deficient in P2X₂ receptors. During hypoxia ATP is released within the ventral respiratory column and acts to maintain respiratory activity in conditions when hypoxia-induced depression of respiration occurs. (iii) The role of ATP in afferent processing in the nucleus tractus solitarii (NTS). It was found that during hypoxia ATP is released on the dorsal surface of the medulla in locations overlaying the NTS, however, blockade of P2 receptors in the NTS had no effect on the respiratory responses evoked by hypoxia. Rhythmic release of ATP that coincided with lung inflation was recorded in the NTS regions where afferents from the slowly adapting lung stretch receptors terminate. Application of ATP increased, while application of P2 receptor antagonists decreased discharge of the NTS second order neurones that receive afferent input from the pulmonary stretch receptors. ATP may therefore be released from the central terminals of slowly adapting lung stretch receptors in the NTS to mediate neurotransmission in the Breuer-Hering reflex pathway. ATP is unlikely however, to be involved in mediating neurotransmission in the carotid chemoreceptor reflex. In summary, the data obtained in our laboratory has revealed the importance of ATP-mediated purinergic signalling in the brainstem mechanisms underlying respiratory control. It emerges that ATP acts as a common mediator of peripheral and central chemosensory transduction and may also contribute to neurotransmission at a first central synapse in the Breuer-Hering reflex pathway.