Brain cells are better protected against systemic acidosis (and alkalosis) than most other cells since they are surrounded by an extracellular fluid which is, in itself, subjected to pH regulation. For all practical purposes, therefore, cerebral intracellular acidosis is endogenous and arises when lactic acid accumulates. This occurs in three main conditions: hypocapnia, epileptic seizures, and hypoxia plus ischaemia. In the first of these, metabolic acidosis is compensatory but in the other two, a moderate or pronounced decrease in pH occurs. In all three, increased glycolytic rate involves activation of phosphofructokinase secondarily to a raised intracellular pH (moderate hypocapnia) or to a perturbation of cerebral energy state (seizures and hypoxia plus ischaemia). In seizure states, accumulation of lactic acid is usually moderate (about 10 mumol g-1). In complete ischaemia, the acidosis is only slightly more pronounced. However, in severe incomplete ischaemia, and in severe hypoxia, the continued substrate supply can lead to excessive accumulation of lactic acid (30-50 mumol g-1). When this occurs, the acidosis contributes to irreversible cell damage.