Despite major advances in understanding how the brain goes awry in disease, identification of therapeutics for neuroprotection in stroke remains an unsolved challenge. A promising strategy to delineate endogenous mechanisms of neuroprotection is to understand adaptive homeostatic transcription induced by sublethal ischemia. Homeostatic adaptation is defined as the body's restorative responses to stress. Activating adaptive homeostatic pathways can lead to transcription of a panoply of genes involved in cell survival and repair, can suppress pro-death signaling, and can stimulate metabolic changes congruent with survival. All of these mechanisms have been shown to be operative in protection induced by sublethal stress. In this context, central mediators of cellular adaptation to hypoxic and viral stress have been implicated in preconditioning. Here we present data that suggest an unexpected convergence in the pathways triggering adaptation to hypoxia and viral infection leading to preconditioning neuroprotection in the CNS.