Ischemic preconditioning is an innate neuroprotective mechanism in which a sub-injurious ischemic exposure increases the brain’s ability to withstand a subsequent, normally injurious ischemic insult. Part of ischemic preconditioning neuroprotection stems from an epigenetic reprogramming of the brain to a phenotype of ischemic tolerance, which results in a gene expression profile different from that observed in the non-injured and ischemia-injured brains. Such neuroprotective reprograming, activated by ischemic preconditioning, requires specific changes in DNA accessibility coordinated with activation of transcriptional activator and repressor proteins, which allows for expression of specific neuroprotective proteins despite a general repression of gene expression. In this review we examine the effects of injurious ischemia and ischemic preconditioning on the regulation of DNA methylation, histone post-translational modifications, and non-coding RNA expression. There is increasing interest in the role of epigenetics in disease pathobiology, and whether and how pharmacological manipulation of epigenetic processes may allow for ischemic neuroprotection. Therefore, a better understanding of the epigenomic determinants underlying the modulation of gene expression that lead to ischemic tolerance or cell death offers the promise of novel neuroprotective therapies that target global reprograming of genomic activity versus individual cellular signaling pathways.