Carbon dioxide (CO 2 ) is an important environmental cue for many organisms but is odorless to humans. It remains unclear whether the mammalian olfactory system can detect CO 2 at concentrations around the average atmospheric level (0.038%). We demonstrated the expression of carbonic anhydrase type II (CAII), an enzyme that catabolizes CO 2 , in a subset of mouse olfactory neurons that express guanylyl cyclase D (GC-D + neurons) and project axons to necklace glomeruli in the olfactory bulb. Exposure to CO 2 activated these GC-D + neurons, and exposure of a mouse to CO 2 activated bulbar neurons associated with necklace glomeruli. Behavioral tests revealed CO 2 detection thresholds of ∼0.066%, and this sensitive CO 2 detection required CAII activity. We conclude that mice detect CO 2 at near-atmospheric concentrations through the olfactory subsystem of GC-D + neurons.