Ischemic preconditioning (PC) of heart and brain is a well-documented phenomenon. However, the mechanism underlying the increased resistance to severe ischemia by a preceding mild ischemic exposure remains unclear. Over a decade ago, we demonstrated the existence of hypoxic PC in the hippocampal slice preparation. Here we report the ability of a short exposure to toxic levels of glutamate to heighten the tolerance of hippocampal slices to a subsequent, longer exposure to the excitotoxin. Glutamate PC could also be induced by a short hypoxic exposure, suggesting a common mechanistic pathway for all PC stimuli. Since glutamate receptor activation and hypoxia increase tissue lactate production, a-cyano-4-hydroxycinnamate was applied during the PC period to completely abolished PC. These results indicate that excitotoxic PC and hypoxic PC share similar mechanisms that possibly involve lactate production and its neuronal utilization.