When all peripheral chemoreceptors are denervated, animals continue to show increased ventilation when made to breathe CO2, indicating that receptors within the brain ("central chemoreceptors") are excited by acidity or changes in CO2. No cells have been identified within the brain that are indisputedly chemoreceptors for CO2 or H+, but there is abundant evidence that respiration can be affected by chemical, electrical, and thermal stimuli applied locally to the ventral surface of the medulla. Furthermore, the actions of traditional central chemical respiratory stimuli can be blunted or abolished after inhibition of neural function within this ventrolateral medullary shell (VMS). The VMS is an integrative region for cardiovascular and respiratory function and may be involved in nociception. The distinction between the former two is not always clear, but recent studies using microinjection techniques seem promising for identifying the respiratory substrates. The many recent advances elucidating anatomic connections between the VMS and other brain regions are important but do not directly address the question of the site of central respiratory chemosensitivity. Knowledge of such connections, however, should provide more definitive opportunities for addressing this question.