This study examined, in cane toads (Bufo marinas), four possible mechanisms responsible for the increase in central pH/CO2-sensitive fictive breathing that occurs following chronic hypercapnia: (1) altered activity from midbrain centres; (2) increases in olfactory CO2 chemoreceptor input; (3) increases in carotid labyrinth chemoreceptor input; (4) increases in carbonic anhydrase activity. Toads were exposed to chronic hypercapnia (3.5% CO2) for 9 days and in vitro brainstem-spinal cord preparations were used to examine central pH/CO2-sensitive fictive breathing. Midbrain transection did not alter the effects of chronic hypercapnia described above, suggesting supramedullary influences were not involved. Olfactory denervation as well as simultaneous exposure to chronic hyperoxia/hypercapnia eliminated the effects of chronic hypercapnia on fictive breathing, suggesting that breathing changes following chronic hypercapnia may result from altered peripheral chemoreceptor input. Carbonic anhydrase inhibition with acetazolamide had different effects following chronic hypercapnia, suggesting a change in carbonic anhydrase activity with chronic hypercapnia.