The retrotrapezoid nucleus (RTN) consists of 2000 glutamatergic neurons that innervate selectively the respiratory centers of the pontomedullary region. These cells are located at the ventral medullary surface in a chemosensitive region previously identified as area M in cats. They selectively express the transcription factor Phox2b. RTN neurons are intrinsically sensitive to acid and are vigorously activated by inputs from the carotid body and from the hypothalamus. Phox2b mutations cause the congenital hypoventilation syndrome (CCHS) a disease characterized by loss of breathing automaticity during sleep and absence of chemoreflexes. The RTN does not develop in a mouse model of CCHS, which also lack central chemoreflexes. In this mini-review I propose a working hypothesis that features the RTN as the critical nodal point for the homeostatic regulation of blood gases. I postulate that RTN always contributes a large fraction of the drive to the respiratory centers and that RTN stabilizes arterial PCO₂ by virtue of the fact that this drive is uniquely and powerfully regulated by pH, both centrally and via inputs from the carotid bodies. This hypothesis incorporates the notion that reduced central command is responsible for matching lung ventilation to the metabolic production of CO₂ and one of its tenets is that when central command is minimal such as during anesthesia or non-REM sleep, breathing automaticity depends entirely on the RTN which is, in turn, solely driven by CO₂. The proposed hypothesis accounts for many physiological observations and for the breathing deficits experienced by CCHS patients.