Glutamate-mediated spreading depression is currently thought to be a key event in the pathogenesis of potential neuronal degeneration in the ischemic 'penumbra'. Glutamate receptor stimulation causes induction of transcription factors that belong to the class of immediate early genes (IEGs), thought to be involved in coupling neuronal excitation to target gene expression. Focal cerebral ischemia elicits a homogeneous expression of several IEGs, prominently in cortex. In the ischemic core, discrepancies are observed between mRNA and protein levels, due to a severe, persistent protein synthesis deficit, preventing the translation of IEG encoded mRNAs. Outside the ischemic core, widespread IEG expression occurs in the entire ipsilateral cortex at mRNA as well as at protein level. This homogeneous expression of transcription factors can be pinpointed to at least two different pathogenetic mechanisms by means of appropriate pharmacological antagonists. Prolonged IEG induction in the 'penumbra', an area in which neurons are metabolically compromised but not yet energy-depleted, cannot be suppressed by the administration of N-methyl-D-aspartate (NMDA) receptor antagonists. In contrast, short-lasting IEG induction in undamaged neurons remote from the ischemic territory, though also caused by ischemia-elicited spreading depression, can be blocked by NMDA receptor antagonists. In both areas, IEG expression identifies neurons destined to survive but is likely to be mediated by different signal transduction pathways, at the receptor, second messenger and/or the DNA level.