Spreading depression (SD) is a slowly propagating wave of neuronal depolarization altering ion homeostasis, blood flow and energy metabolism without causing irreversible damage of the tissue. As SD has been implicated in several neurological diseases including migraine and stroke, understanding these disorders requires systematic knowledge of the processes modified by SD. Thus, we induced repetitive SD in the rat cerebral cortex by topical application of 3 M KCl for ∼2 h and evaluated the kinetics of SD-induced changes in cortical gene expression for up to 30 days using Affymetrix RAE230A arrays. The temporal profile showed a rapid expression of immediate early genes, genes associated with inflammation, metabolism, stress and DNA repair, ion transport, and genes that play a role in growth/differentiation. Stress-response genes could still be detected after 24 h. At this time, induced genes were mainly related to the cell membrane and adhesion, or to the cytoskeleton. A subset of genes was still affected even 30 days after SD. Real-time polymerase chain reactions and immunohistochemistry confirmed the microarray results for several of the transcripts. Our findings demonstrate a temporal pattern of gene expression which might promote tissue remodeling and cortical plasticity, and might probably account for the mediation of neuronal tolerance towards subsequent ischemia.