The regulation of breathing relies upon chemical feedback concerning the levels of CO2 and O2. The carotid bodies, which detect O2, provide tonic excitation to brainstem respiratory neurons under normal conditions and dramatic excitation if O2 levels fall. Feedback for CO2 involves the carotid body and receptors in the brainstem, central chemoreceptors. Small increases in CO2 produce large increases in breathing. Decreases in CO2 below normal can, in sleep and anesthesia, decrease breathing, even to apnea. Central chemoreceptors, once thought localized to the surface of the ventral medulla, are likely distributed more widely with sites presently identified in the: (1) ventrolateral medulla; (2) nucleus of the solitary tract; (3) ventral respiratory group; (4) locus ceruleus; (5) caudal medullary raphé; and (6) fastigial nucleus of the cerebellum. Why so many chemoreceptor sites? Hypotheses, some with supporting data, include the following. Geographical specificity; all regions of the brainstem with respiratory neurons contain chemoreceptors. Stimulus intensity; some sites operate in the physiological range of CO2 values, others only with more extreme changes. Stimulus specificity; CO2 or pH may be sensed by multiple mechanisms. Temporal specificity; some sites respond more quickly to changes on blood or brain CO2 or pH. Syncytium; chemosensitive neurons may be connected via low resistance, gap junctions. Arousal state: sites may vary in effectiveness and importance dependent on state of arousal. Overall, as judged by experiments of nature, and in the laboratory, central chemoreceptors are critical for adequate breathing in sleep, but other aspects of the control system can maintain breathing in wakefulness.