The role of changes of intracellular pH (pHi) as the proximal signal in central chemosensitive neurons has been studied. pHi recovery from acidification is mediated by Na+/H+ exchange in all medullary neurons and pHi recovery from alkalinization is mediated by Cl−/HCO3− exchange in most medullary neurons. These exchangers are more sensitive to inhibition by changes in extracellular pH (pHo) in neurons from chemosensitive regions compared to those from nonchemosensitive regions. Thus, neurons from chemosensitive regions exhibit a maintained intracellular acidification in response to hypercapnic acidosis but they show pHi recovery in response to isohydric hypercapnia. A similar pattern of pHi response is seen in other CO2/H+-responsive cells, including glomus cells, sour taste receptor cells, and chemosensitive neurons from snails, suggesting that a maintained fall of pHi is a common feature of the proximal signal in all CO2/H+-sensitive cells. To further evaluate the potential role of pHi changes as proximal signals for chemosensitive neurons, studies must be done to: determine why a lack of pHi recovery from hypercapnic acidosis is seen in some nonchemosensitive neurons; establish a correlation between hypercapnia-induced changes of pHi and membrane potential (Vm); compare the hypercapnia-induced pHi changes seen in neuronal cell bodies with those in dendritic processes; understand why the Vm response to hypercapnia of many chemosensitive neurons is washed out when using whole cell patch pipettes; and employ knock out mice to investigate the role of certain proteins in the CO2/H+ response of chemosensitive neurons.