Central respiratory chemoreception (CRC) is the mechanism by which brain pCO2 regulates breathing (Feldman et al. 2003). Central chemoreception clearly relies on changes in brain extracellular fluid pH but the molecular, cellular and network basis of CRC is far from understood. The very existence of bona fide central chemoreceptors can even be legitimately questioned. Indeed, given the widespread effect of pH on brainstem neurons in vitro, one can still persuasively argue that CRC may be an emergent property of the central respiratory pattern generators (CPGs) caused by the cumulative effects of pH on most if not all of its component neurons. The contrary and more prevalent view is that CRC relies on one or more clusters of neurons that are primarily responsible for the exquisite sensitivity of the respiratory network to CO2 (Feldman et al. 2003). The importance of these clusters may have to do with the dynamic range of their discharge in response to changes in ECF pH and/or to some particular combination of connectivity and transmitter effectiveness. None of these characteristics absolutely requires that respiratory chemoreceptor neurones possess unique pH-sensitive conductances and, in fact, no such conductance has been identified so far. Research started in the 1960s suggests that a group of central chemoreceptors that regulates breathing and cardiovascular function resides at the ventral medullary surface (VMS) under the facial motor nucleus (Loeschcke, 1982). In this talk I shall consider whether these elusive VMS chemoreceptors reside in the brain region recently identified as the retrotrapezoid nucleus (RTN). RTN neurons are glutamatergic propriobulbar interneurons that innervate the entire ventral respiratory column and selected regions of the dorsolateral pons and nucleus of the solitary tract (NTS)(Mulkey et al. 2004). These neurons are located very close to ventral surface and have extensive dendrites within the marginal layer of the brainstem (Mulkey et al. 2004). They respond vigorously to CO2 in vivo and their response is unaffected by procedures that silence the CPGs such as the administration of opiate agonists or antagonists of ionotropic glutamatergic receptors (Mulkey et al. 2004). RTN neurons display numerous types of respiratory-related patterns (Guyenet et al. 2005). These patterns are caused by inputs from multiple types of CPG neurons, the majority of which are probably inhibitory. In the absence of CPG activity and peripheral chemoreceptor input, RTN neurons discharge tonically at a rate that is inversely proportional to arterial pH (average threshold: pH 7.5) (Guyenet et al. 2005). However, RTN neurons also receive excitatory inputs from peripheral chemoreceptors via a direct pathway from the NTS that bypasses the CPGs. Thus RTN neurons have the properties of a chemosensory integrative center that is independent of the CPGs. In rat and mouse slices, RTN neurons are silent at pH 7.5, they are vigorously excited by acidification and their discharge pattern is tonic. When examined at physiological temperature, the dynamic range of their response to pH is similar in vitro and in vivo (Guyenet et al. 2005). Under conditions of reduced synaptic activity (tetrodotoxin), acidification produces an inward current in RTN neurons which is attributable to the closure of a resting potassium conductance, currently unidentified (Mulkey et al. 2004). The presence of purinergic receptor antagonists (PPADS and others) does not modify the pH sensitivity of RTN neurons in slices (Guyenet et al. 2005) but these cells are activated by the P2Y-selective agonist UTP (Mulkey, Guyenet and Bayliss, unpublished). In conclusion, RTN neurons detect brain pCO2 at least in part by virtue of an intrinsic pH sensitivity that involves an unknown resting potassium conductance. We found no evidence that a purinergic paracrine mechanism contributes to their chemosensitivity in vitro. However, these neurons probably express P2Y receptors and therefore, their activity could be up-regulated by ATP in vivo as proposed by Gourine and others (Gourine et al. 2005). RTN neurones also respond to arterial blood gases via a very direct excitatory pathway from carotid peripheral chemoreceptors and they receive a feed-back from the CPG. These characteristics are consistent with the view that RTN is a chemosensory integrating center. The exact role of RTN neurones is not fully clarified by our experiments however. Given their projections and location, it is conceivable that RTN neurons could be encoding some of the chemical drive to breathe but they could also play a role in cardiorespiratory coupling.