Proper function of hypoglossal motoneurons (XII MNs) innervating tongue muscles is critical for respiratory control of the airway. Morphological and electrophysiological properties of XII MNs change during postnatal development, as do modulatory systems. Despite these changes, the system producing respiratory movements must remain fully functional throughout life. Modulatory systems have therefore received considerable attention since coordination of their development with a developing neuromuscular system may be critical for maintenance of continuous, efficient breathing. Developmental modulation of XII inspiratory activity by three transmitter systems is examined. Thyrotropin-releasing hormone (TRH) mediates an increase in MN input resistance (RN) in juvenile but not neonate MNs, and this likely underlies the developmental increase in TRH potentiation of inspiratory activity. Norepinephrine (NE) potentiation of inspiratory activity, which in the neonate is produced in part by an alpha 1-mediated increase in RN, also increases postnatally. Effects of purinergic transmission on XII inspiratory activity remain constant during the first 2 weeks of postnatal development. Adenosine-triphosphate (ATP) produces tonic excitation and inspiratory potentiation that likely result from activation of postsynaptic P2 receptors. A secondary inhibitory effect likely results from hydrolysis of ATP to adenosine and activation of presynaptic A1 adenosine receptors. The functional relevance of these postnatal changes is discussed.