Gender-based differences in patient response to injury/disease have long been recognized both in clinical and experimental settings [1, 2]. Despite this, some remain skeptical on the role of gender in the overall outcome of patients [1, 3]. From an analysis of more than 150,000 trauma patients, it was concluded that male patients are at higher risk of death as compared to female patients following blunt trauma . Similarly, other studies have also indicated that females are more resistant to sepsis as compared to males [5, 6]. However, gender was not found to be a significant factor in the outcome of trauma patients in some other studies [7, 8]. Thus, the role of gender in the outcome of trauma patients remains somewhat controversial. In contrast, the findings from experimental studies clearly indicate that gender plays a critical role in the host response to major injury [1, 2]. These studies have shown that immune and cardiovascular functions are suppressed following trauma-hemorrhage in mature males, ovariectomized and aged females, while both immune and cardiac functions are maintained in proestrus females under those conditions [1, 3, 9, 10]. Similarly, liver functions following trauma-hemorrhage were depressed in males, but were maintained in proestrus females. Moreover, the survival rate of proestrus females subjected to sepsis after trauma-hemorrhage is significantly higher than age-matched males or ovariectomized females. In this chapter, we will review studies delineating the potential mechanisms by which male and female sex hormones influence immune and other organ functions following trauma-hemorrhage. © 2007 Springer Science + Business Media Inc.