The brain regulates breathing in response to changes in CO/H by a process referred to as respiratory chemoreception. The retrotrapezoid nucleus (RTN) is essential for this function. RTN neurons are intrinsically activated by CO/H. Astrocytes contribute as well, by providing a CO/H-dependent purinergic drive to augment neural activity directly and indirectly by causing vasoconstriction. Here, we summarize preclinical studies in rodents that identify: (i) mechanisms of CO/H detection by RTN neurons; (ii) how this information is integrated at the neural network level; and (iii) how RTN neural activity is shaped by CO/H sensitive astrocytes. We also discuss how disruption of RTN chemoreception might contribute to breathing problems in disease, and highlight the therapeutic potential of targeting CO/H-dependent and -independent regulatory elements of RTN neurons.