The regulation and defence of intracellular pH is essential for homeostasis. Indeed, alterations in cerebrovascular acid–base balance directly affect cerebral blood flow (CBF) which has implications for human health and disease. For example, changes in CBF regulation during acid–base disturbances are evident in conditions such as chronic obstructive pulmonary disease and diabetic ketoacidosis. The classic experimental studies from the past 75+ years are utilized to describe the integrative relationships between CBF, carbon dioxide tension (PCO₂), bicarbonate (HCO₃^–) and pH. These factors interact to influence (1) the time course of acid–base compensatory changes and the respective cerebrovascular responses (due to rapid exchange kinetics between arterial blood, extracellular fluid and intracellular brain tissue). We propose that alterations in arterial [HCO₃^–] during acute respiratory acidosis/alkalosis contribute to cerebrovascular acid–base regulation; and (2) the regulation of CBF by direct changes in arterial vs. extravascular/interstitial PCO₂ and pH – the latter recognized as the proximal compartment which alters vascular smooth muscle cell regulation of CBF. Taken together, these results substantiate two key ideas: first, that the regulation of CBF is affected by the severity of metabolic/respiratory disturbances, including the extent of partial/full acid–base compensation; and second, that the regulation of CBF is independent of arterial pH and that diffusion of CO₂ across the blood–brain barrier is integral to altering perivascular extracellular pH. Overall, by realizing the integrative relationships between CBF, PCO₂, HCO₃^– and pH, experimental studies may provide insights to improve CBF regulation in clinical practice with treatment of systemic acid–base disorders.