Nitric oxide (NO) is one of the so called atypical neurotransmitters which also include other gaseous molecules such as carbon monoxide, and as such is a highly promiscuous messenger. NO production in the brain can originate from activation of the neuronal NO synthase (nNOS) isoform contained within neurones, which is calcium-dependent and has been shown to be present in a variety of brain areas (Campese et al. 2007). A property of NO is its ability to freely cross biological membranes once produced. As a result its modulatory actions within the brain are through pre- and postsynaptic effects. These properties all make NO an excellent candidate in synchronizing neuronal discharge in a population of neurones which may be an important factor in the organization of oscillatory activity within a central pattern generator as already described. Indeed, NO has been shown to modulate numerous centrally based rhythmic activities such as fœtal swallowing, feeding in pond snails, thalamocortical neurons, locomotion and respiration. Our interest is the role of NO within the brainstem respiratory network. Much of the literature has described a key role for NO in the ventilatory response to hypoxia but few studies have defined a putative role during normoxia. The use of knock-out mice for deleting the different isoforms of NOS have shown some or no modifications of basal ventilation even when multiple NOS knock out mice were tested (Tsuisui et al. 2006). Furthermore, in such studies the effect of NO is not clearly localized to the peripheral or central nervous system or both. To date no studies have been performed at the neuronal level in the intact respiratory network to reveal the effect(s) of NO on respiratory neurone discharge. Thus the goal of my presentation will be to describe the effects of NO on both motor output and single respiratory neurones within the medullary respiratory network studied in vitro and in situ, and to provide evidence for the biochemical pathways involved in mediating the effects of NO during normoxia. I will show that in an in vitro rhythmic medullary slice containing the Pre-Bötzinger complex, basal respiratory network motor output activity is modulated by NO from birth with an excitatory effect on inspiratory neuronal bursting. Evidence suggests that this excitatory effect involves a NO-mediated reinforcement of the NMDA component of inspiratory discharge. Results obtained at the neuronal level from an intra-arterially perfused anaesthetised juvenile rat preparation show that NO can have both inhibitory and excitatory effects on all types of respiratory neurone. These effects can be attributed to two known and distinct biochemical pathways that involve soluble guanylate cyclase and peroxynitrite respectively. Moreover, NO modulates both GABA and NMDA triggered responses but surprisingly this was limited to two specific types of respiratory neurones which have been ascribed major roles in the onset and offset of the inspiratory and expiratory phases and seemed essential for generating the basic respiratory oscillation in adult mammals (Richter et al. 1992). These results compliment the previously described role of NO during the ventilatory response to hypoxia by strongly supporting NO as major modulator of respiratory neuronal bursting during normoxia. Furthermore, the data indicate specific targeting of NO actions on ligand mediated responses in two types of respiratory neurones involved in respiratory phase transition mechanisms.