Studies in human as well as animal models demonstrate that females in the proestrus cycle (i.e., with high estrogen) tolerate trauma-hemorrhage and sepsis far better than males. The female sex steroid, estrogen, is the significant factor contributing to this observed gender difference in outcome. One reason for the lack of significant gender association in some clinical studies is the possibility of heterogeneity of the population in terms of their hormonal status at the time of injury. Several experimental investigations have revealed that androgens produce immune and cardiovascular depression after trauma-hemorrhage. However, the use of an androgen receptor antagonist after trauma-hemorrhage has salutary effects of immune and cardiovascular function. Likewise, estrogen produces beneficial effects on immune and cardiovascular function after trauma-hemorrhage and significantly decreases mortality rates from subsequent sepsis. The salutary effects of estrogen after trauma-hemorrhage have been shown to be due to both genomic and nongenomic effects. Thus, the use of an estrogen or androgen receptor antagonist as an adjunct after trauma-hemorrhage is a safe and novel approach for restoring immune and cardiovascular function after trauma-hemorrhage and for decreasing the mortality from subsequent sepsis. © 2008 International Anesthesia Research Society.