Focal ischaemic injury in the brain is related to both the intensity and the duration of the decrement in cerebral blood flow. The ischaemic penumbra, an area characterised by levels of blood flow slightly greater than the ischaemic core itself, is a zone exhibiting preserved or even accentuated metabolic rate, apparently driven by recurrent ischaemic depolarisations. Excitatory amino acid neurotransmitter release and raised levels of oxygen radical activity occur within it. The penumbra represents that region of the focal ischaemic lesion which is potentially amenable to metabolic neuroprotection, and several classes of neuroprotective agents are currently under clinical evaluation for stroke. As the untreated penumbra deteriorates over time, animal studies indicate that therapy should be administered within a therapeutic window of no more than 3–6 h from stroke onset if it is to be successful.