The incidence of stroke involving CNS white matter is relatively high, yet there are currently no protective treatments that limit irreversible dysfunction in white matter stroke. The events that lead from the loss of oxygenation to irreversible injury in white matter are now well characterized. Anoxic injury in white matter follows the accumulation of toxic levels of Ca2+ within intracellular compartments. This Ca2+ influx is triggered by depolarization, influx of Na+ and subsequent backward operation of a membrane protein, the Na+/ Ca2+ exchanger, which normally moves Ca2+ out of cells. Anoxic injury in white matter is partly under the control of autoprotective substances released by white matter. In particular, GABA and adenosine are released from endogenous stores as a result of anoxia and recruit a cascade of intracellular events which act to increase resistance to anoxic injury. Recovery of function in white matter following anoxic insults can be improved by application of exogenous GABA or adenosine, and by exposure to drugs which inhibit reuptake to increase the levels of GABA and adenosine in the extracellular space. This autoprotective system is thus open to manipulation via pharmacological strategies that may prove to be clinically useful.