The ventral surface of the rostral medulla oblongata has been suspected since the 1960s to harbor central respiratory chemoreceptors [i.e., acid-activated neurons that regulate breathing to maintain a constant arterial PCO₂ (PaCO₂)]. The key neurons, a.k.a. the retrotrapezoid nucleus (RTN), have now been identified. In this review we describe their transcriptome, developmental lineage, and anatomical projections. We also review their contribution to CO₂ homeostasis and to the regulation of breathing automaticity during sleep and wake. Finally, we discuss several mechanisms that contribute to the activation of RTN neurons by CO₂ in vivo: cell-autonomous effects of protons; paracrine effects of pH mediated by surrounding astrocytes and blood vessels; and excitatory inputs from other CO₂-responsive CNS neurons.