CO2 central chemoreceptors (CCRs) play a critical role in respiratory and cardiovascular controls. Although the primary sensory cells and their neuronal networks remain elusive, recent studies have begun to shed insight into the molecular mechanisms of several pH sensitive proteins. These putative CO2/pH-sensing molecules are expressed in the brainstem, detect P(CO2) at physiological levels, and couple the P(CO2) to membrane excitability. Functional analysis suggests that multiple CO2/pH-sensing molecules are needed to achieve high sensitivity and broad bandwidth of the CCRs. In contrast to the diversity of pH sensitive molecules, molecular mechanisms for CO2 sensing are rather general. The sensing molecules detect pH changes rather than molecular CO2. One or a few titratable amino acid residues in these proteins are usually involved. Protonation of these residues may lead to a change in protein conformation that is coupled to a change in channel activity. Depending on the location of the protonation sites, a membrane protein can detect extra- and/or intracellular pH.