Carotid bodies are the sensory organs for detecting O2 levels in arterial blood. Hypoxemia increases the sensory nerve activity of the carotid body leading to reflex stimulation of breathing and elevation of blood pressure. This presentation focuses on the roles of endogenous carbon monoxide (CO) and hydrogen sulfide (H2S) in hypoxic sensing by the carotid body. In mammalian cells, CO is generated during oxidative cleavage of heme by heme oxygenases (HO) and molecular oxygen is essential for this reaction. Two forms of HO have been identified including an inducible HO1, which resembles stress-inducible protein HSP-32, and a constitutively expressed HO2. Glomus cells, the site of O2 sensing in the carotid body, express HO2. Hypoxia decreases CO generation in a stimulus-dependent manner. Rats treated with HO-inhibitor and mice lacking HO2 (HO2 knockout mice) exhibit increased baseline carotid body activity and augmented sensory response to hypoxia, suggesting that endogenous CO is physiological inhibitor to the carotid body activity. Cystathionine β-synthase (CBS) and cystathionine-γ-lyase (CSE) are the major enzymes responsible for generation of endogenous H2S. Hypoxia increases H2S generation in the carotid body in a stimulus-dependent manner (Peng et al. 2010). Although glomus cells express both CBS and CSE, genetic deletion of CSE alone is sufficient to prevent hypoxia-evoked H2S generation as well as hypoxic sensing by the carotid body (Peng et al. 2010). Exogenous application of H2S donor stimulates the carotid body activity with a time course and magnitude similar to hypoxia. These observations suggest that endogenous H2S is a physiological mediator of carotid body sensory response to hypoxia. [Ru(CO)3Cl2]2, a CO donor inhibited, whereas CrIIIMP, a HO inhibitor, stimulated H2S generation in the carotid body. The enhanced H2S generation by HO inhibitor was absent in CSE knockout mice suggesting that hypoxia-evoked H2S generation in the carotid body requires the interaction of HO2 with CSE. Based on these studies it is proposed that hypoxic sensing by the carotid body requires protein-protein interactions between HO2 and CSE working in concert as a “chemosome”. Supported by NIH-HL-76537, HL-90554, and HL-86493.