© Springer International Publishing Switzerland 2015. All rights are reserved. The sex of a patient is increasingly recognized as a major factor determining the outcome of sepsis. Experimental findings indicate that female rodents in the proestrus cycle (i.e., when the estrogen levels are at their highest) are more tolerant than their male counterparts to major injuries. Several lines of evidence indicate that male and female humans and rodents respond differently to shock. In this regard, findings from clinical studies suggest that premenopausal women have a lower incidence of infection, pneumonia, sepsis, and multiple organ failure than men under those conditions. Sex differences have also been noted in organ function, and the potential reasons for these differences have been the subject of extensive research. This chapter deals with sepsis following trauma and injury and examines the following: (1) the evidence for sex differences following trauma and sepsis and (2) the mechanisms by which gender/sex hormones provide organ protection under those conditions. The available information indicates that sex steroids modulate organ function following injury. Thus, modulation of the prevailing hormone milieu immediately following injury appears to be a novel therapeutic approach for improving the outcome following those conditions.