In the surroundings of focal ischemic lesions, repetitive spreading depression (SD)-like depolarizations occur. These depolarizations are triggered by the anoxic release of potassium and excitatory amino acids from the infarct core, and they are propagated over the whole hemisphere at a speed of approximately 3 mm/min. The associated fluid shifts can be detected by diffusion-weighted magnetic resonance imaging (MRI) and correlate with an aggravation of the metabolic disturbance. In the peripheral, normally perfused brain regions of the infarcted hemisphere, the metabolic workload of SD is coupled to a parallel increase of blood flow, ensuring undisturbed oxygen supply. In the periinfarct penumbra, in contrast, the reduced hemodynamic capacity of the collateral system prevents adequate oxygenation and results in episodes of tissue hypoxia. Periinfarct SDs induce expression of immediate early genes in all brain regions except the ischemic core, i.e, in the penumbra and the surrounding normal brain tissue. In the penumbra, the hypoxic episodes evoked by SDs produce an additional stress response that is reflected by the expression of stress proteins and the suppression of global protein synthesis. In the most severely ischemic parts of the penumbra, periinfarct depolarizations may turn into terminal depolarization, resulting in a stepwise expansion of the infarct core. Postischemic application of N-methyl-D-aspartate (NMDA) and non-NMDA glutamate receptor antagonists suppresses periinfarct depolarizations, reverses the penumbral suppression of protein synthesis, and reduces infarct size. These observations demonstrate that periinfarct depolarizations aggravate focal ischemic injury and suggest that therapeutic suppression of these depolarizations minimizes infarct size.