In mammals, peripheral arterial chemoreceptors located primarily in the carotid body (CB) play a key role in the maintenance of blood PO₂, PCO₂, and pH homeostasis, via the reflex control of ventilation. The polymodal nature of this sensory organ is further emphasized by more recent evidence suggesting a role in the sensing of blood osmolarity, temperature, and glucose. The CB contains clusters of chemoreceptor (type 1) cells which receive afferent sensory innervation from the petrosal ganglion via the carotid sinus nerve (CSN), a branch of the glossopharyngeal (GPN) nerve. The afferent CSN discharge in turn provides the peripheral input to the central pattern generator in the brainstem, leading to the control of respiration. Since the pioneering studies of Fernando De Castro and Corneille Heymans in the 1920’s and 1930’s on the structure and function of the CB, there has been considerable interest in the transduction and neurotransmitter mechanisms that operate during chemoexcitation. In this lecture, I will begin with a brief historical overview of some of the key studies that led to our current understanding of the role of CB neurotransmitters and neuromodulators in shaping sensory output and CSN discharge. While it is now generally accepted that the neurotransmitter ATP and P2X purinergic receptors play important roles in chemoexcitation, other CB transmitters and modulators including ACh, dopamine (DA), 5-HT, adenosine, and GABA are also thought to contribute to the afferent response. I will also review studies from my laboratory based on a unique co-culture model containing rat type 1 cell clusters and petrosal neurons, that contributed to current ideas and working models on sensory processing in the CB. In addition to the ‘afferent excitatory’ pathway discussed above, the CB also receives an ‘efferent inhibitory’ innervation via a plexus of neuronal nitric oxide synthase (nNOS) -positive fibers originating from autonomic neurons embedded within the GPN nerve (i.e. GPN neurons). Much less is known about the mechanisms underlying activation of this pathway, leading to release of nitric oxide (NO) and inhibition of CB receptors. I will review some of our more recent studies, based on a different co-culture model of type 1 cell clusters and isolated GPN neurons, suggesting an additional involvement of ATP and P2X receptors in the generation of the NO signal and negative feedback inhibition of CB receptors. The reasons for this complex pattern of regulation of CB function by multiple neuroactive agents are presently unclear. Conceivably, they may contribute to the mechanisms underlying CB plasticity during patterned stimulation, e.g. chronic sustained hypoxia and chronic intermittent hypoxia, as experienced during cardiorespiratory disorders such as chronic obstructive pulmonary disease and sleep apnea.