Epigenetic remodeling and modifications of chromatin structure by DNA methylation and histone modifications represent central mechanisms for the regulation of neuronal gene expression during brain development, higher-order processing, and memory formation. Emerging evidence implicates epigenetic modifications not only in normal brain function, but also in neuropsychiatric disorders. This review focuses on recent findings that disruption of chromatin modifications have a major role in the neurodegeneration associated with ischemic stroke and epilepsy. Although these disorders differ in their underlying causes and pathophysiology, they share a common feature, in that each disorder activates the gene silencing transcription factor REST (repressor element 1 silencing transcription factor), which orchestrates epigenetic remodeling of a subset of 'transcriptionally responsive targets' implicated in neuronal death. Although ischemic insults activate REST in selectively vulnerable neurons in the hippocampal CA1, seizures activate REST in CA3 neurons destined to die. Profiling the array of genes that are epigenetically dysregulated in response to neuronal insults is likely to advance our understanding of the mechanisms underlying the pathophysiology of these disorders and may lead to the identification of novel therapeutic strategies for the amelioration of these serious human conditions.