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Preconditioning is injury induced protection from subsequent injury. During preconditioning protective cellular responses to injury are up regulated resulting in acute and delayed defense against further damage. Several studies indicate that females experience a protective advantage after acute insult compared to males. Despite evidence of gender differences in acute injury, relatively few studies have evaluated whether there are sex differences in preconditioning. Variations in patients’ pre-morbid preconditioning status may explain outcome variations that are not apparent in small animal studies. This review discusses the differences in response to acute injury experienced by males and females, the basic mechanisms of preconditioning, and the sex differences in the mechanisms of preconditioning.