The mammalian carotid body is a small chemosensory organ that helps maintain the chemical composition of arterial blood via reflex control of ventilation. Thus, in response to decreased PO2 (hypoxia), increased PCO2 (hypercapnia), or decreased pH (acidity), chemoreceptor glomus or type I cells become stimulated and release neuroactive agents that excite apposed sensory terminals of the carotid sinus nerve. The resulting increase in afferent discharge ultimately leads to corrective changes in ventilation so as to maintain blood gas and pH homeostasis. Recent evidence that the organ can also sense low glucose further emphasizes its role as a polymodal sensor of blood-borne stimuli. The chemoreceptors occur in organized cell clusters that receive sensory innervation from petrosal afferents and are intimately associated with the blood supply. Additionally, synaptic specializations between neighboring receptor cells allow for autocrine and paracrine regulation of the sensory output. Though not without controversy, significant progress has been made in elucidating the various chemotransductive pathways, as well as the neurotransmitter and neuromodulatory mechanisms that translate the receptor potential into an afferent sensory discharge. Progress in the latter has been hampered by the presence of a wide variety of endogenous ligands, and an even broader spectrum of receptor subtypes, that apparently help shape the chemoreceptor output and afferent discharge. This review will highlight recent advances in understanding the role of these neuroactive ligands in carotid body function.