BACKGROUND: The development of metabolic perturbations following severe trauma/sepsis leading to decreased energy production, hyperglycemia, and lipolysis is often rapid. Gender is increasingly recognized as a major factor in the outcome of patients suffering from trauma/sepsis. Moreover, sex hormones influence energy, glucose, and lipid metabolism. Metabolic modulators, such as peroxisome proliferator-activated receptor-γ coactivator-1 and peroxisome proliferator-activated receptor-α, which are required for mitochondrial energy production and fatty acid oxidation, are regulated by the estrogen receptor-β and consequently contribute to cardioprotection following trauma hemorrhage. Additionally, sex steroids regulate inflammatory cytokines that cause hypermetabolism/catabolism via acute phase response, leading to increased morbidity and mortality. MEASUREMENTS: This article examines the following: (1) the evidence for gender differences; (2) energy, glucose, and lipid metabolism and the acute phase protein response; (3) the mechanisms by which gender/sex hormones affect the metabolic modulators; and (4) the tissue-specific effect of sex hormone receptors and the effect of genomic and nongenomic pathways of sex hormones following trauma. RESULTS AND CONCLUSIONS: The available information indicates that sex steroids not only modulate the immune/cardiovascular responses but also influence various metabolic processes following trauma. Thus, alteration or modulation of the prevailing hormone milieu at the time of injury appears to be a novel therapeutic adjunct for improving outcome after injury. © 2007 Lippincott Williams & Wilkins, Inc.