The carotid bodies (CB) are paired secondary sensory receptors whose natural stimuli are decreases in arterial PO2 and increases in arterial PCO2 and [H+]. Chemoreceptor cells detect the stimuli and transduce them into specific patterns of release of neurotransmitters. Upon their release, neurotransmitters activate the sensory nerve endings of the carotid sinus nerve (CSN) to set a level of action potential frequency that conveys information on the nature, intensity and time course of the stimuli to brain stem nuclei. Brainstem respiratory and vasomotor control centres integrate CB-CSN incoming information to generate reflex ventilatory and cardiovascular responses aimed to maintain blood gases and pH the closest possible to normality. At the cellular level, probably the most relevant question physiologically deals with the molecular mechanisms operating in the detection-sensing of natural stimuli in chemoreceptor cells. Intimately related to the sensing of natural stimuli is the definition of the mechanisms which couple the sensing devices to the chemoreceptor cells effectors, including the exocytotic machinery responsible for the release of neurotransmitters, as well as their regulation by second messengers. Finally, it is also of prime interest the knowledge of the relative importance of each neurotransmitter in setting the CSN activity and its relation with the intensity of stimulation. We will present some recent information generated in our laboratory related to these fundamental aspects of CB cellular physiology. Animal protocols were approved by the University of Valladolid Institutional Committee for Animal Care and Use following international laws and policies (Guide for the Care and Use of Laboratory Animals, National Institutes of Health, 85-23, 1985). In every instance animals were anaesthetised by intraperitoneal injection of sodium pentobarbital, 40 mg/Kg for guinea pigs and 60 mg/Kg for rats. Since our initial description of the O2-sensitive K+ currents in chemoreceptor cells, they have been considered key pieces in the O2-sensing and transduction machinery in these cells. However, pharmacological data and particularly information gathered from animals genetically deficient in different K+ channels would appear to drive the attention to alternative sensor-effector mechanisms. In this front we have chosen guinea pigs, species which have naturally ablated their ventilatory response to hypoxia, and found that their chemoreceptor cells, which are responsive to depolarizing stimuli (by increasing their intracellular Ca2+ and increasing their release of neurotransmitters), do not respond to hypoxia, and more importantly, their voltage-dependent K+ currents lack O2-sensitive components. Hydrogen sulfide (H2S) has recently been recognized as a regulator of the CB hypoxic responses. We have observed that H2S donors (NaHS and GYY4137) activate rat chemoreceptor cells increasing their intracellular Ca2+ and promoting their release of neurotransmitters. Hydroxycobalamin, which reacts with H2S to form sulfocobalamin, abolishes the effects of sulfide donors, does not affect the Ca2+ and release responses elicited by high external K+, and inhibits by about 60% the response elicited by hypoxia. These findings locate H2S actions in the transduction cascade upstream of depolarization. At the neurotransmission level, we have found that rat chemoreceptor cells release adenosine and ATP in a manner dependent on the intensity of hypoxic stimuli: adenosine is released preferentially in response to hypoxia of low and moderate intensity, while ATP release increases in direct proportion to the intensity of hypoxia. Consistent with the release pattern, selective antagonists of adenosine receptors are maximally effective to inhibit CSN discharges elicited by moderate hypoxia while ATP receptor antagonists inhibit by a greater percentage the CSN activity elicited by intense hypoxia.