In a recent proteomic characterization of ischemic-tolerant rodent brains, we discovered an enriched presence of repressive transcriptional regulator proteins with essential roles as epigenetic regulators inducing tolerance to ischemia in brain (1). We further showed their robust, dynamic and differential changes under different ischemic conditions in brain. In the present work, we aimed to characterize the de novo proteome, the proteome that presents early during the induction of ischemic tolerance. These would be the proteomic changes of newly synthesized proteins at the initiation of the tolerant phenotype. Identification of effectors of this phase of tolerance induction bears the best promise of identifying therapeutic targets for treating acute stroke when patients present to hospital. We compare these de novo results to those in fully developed tolerant brains.