Elucidation of the endogenous cell survival pathways involved in ischemic tolerance (preconditioning) and postconditioning has significant clinical implications for preventing neuronal damage in susceptible patients. Ischemic tolerance is a phenomenon in which the brain protects itself against future injury by adapting to low doses of noxious insults. Ischemic postconditioning is defined as brief periods of reperfusion alternating with re-occlusion applied during the very early minutes of reperfusion that mechanically alters the hydrodynamics of reperfusion. Similar pathways and molecules play a role in pre-and postconditioning but their roles and timing are different in each conditioning. Understanding the neuroprotective effects of mechanisms underlying conditioning has been elusive, but NMDA receptor activation, nitric oxide, inflammatory cytokines, and suppression of the innate immune system appear to have a role. Reactive oxygen species and classical ligand stimuli play a role in postconditioning with KATP channels and protein kinase C pathways acting as mediators.