Cerebral blood flow (CBF) and its distribution is highly sensitive to changes in the partial pressure of arterial carbon dioxide (PaCO₂). This physiological response - termed cerebrovascular CO₂ reactivity - is a vital homeostatic function that helps regulate and maintain central pH, and therefore affects the central chemoreceptor stimulus. CBF increases with hypercapnia to wash out CO₂ from brain tissue thereby attenuating the rise in central PCO₂, while hypocapnia causes cerebral vasoconstriction which reduces CBF and attenuates the fall of brain tissue PCO₂. Cerebrovascular reactivity and ventilatory response to PaCO₂ are therefore tightly linked so that the regulation of CBF has an important role in stabilizing breathing during fluctuating levels of chemical stimuli. Indeed, recent reports indicate that cerebrovascular responsiveness to CO₂, primarily via its effects at the level of the central chemoreceptors, is an important determinant of eupnoeic and hypercapnic ventilatory responsiveness in otherwise healthy humans during wakefulness, sleep, exercise and at high altitude. In particular, reductions in cerebrovascular responsiveness to CO₂, that provoke an increase in the gain of the chemoreflex control of breathing may underpin breathing instability during central sleep apnea observed in patients with congestive heart failure and upon ascent to high altitude. In this review, we summarize the major factors which regulate CBF in order to emphasize the integrated mechanisms - in addition to PaCO₂ - by which CBF is controlled. Detailed discussion is given regarding the assessment and interpretation of cerebrovascular reactivity to CO₂. Next, we provide a detailed update on the integration of the role of cerebrovascular CO₂ reactivity and CBF in regulating chemoreflex control of breathing in health and disease. Finally, we describe the use of a newly developed steady-state modeling approach to examine the effects of changes in CBF on the chemoreflex control of breathing and suggest avenues for future research.