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Glucocorticoids, the major effector hormones of the stress system, influence almost all aspects of mammalian physiology. These steroids exert their effects on a large network of primary, secondary, and tertiary target genes, encompassing up to 20% of the expressed genome in a tissue. New evidence shows quantitative and qualitative gender-specific differences in the actions of glucocorticoids on the rat liver transcriptome, suggesting that the pervasive actions of these hormones are modulated by gender, both as an inherent property of the target tissues and as a result of exposure of these tissues to estrogens and possibly also androgens. Generally, albeit not always, female mammals have more robust behavioral and somatic responses to stress and more potent immune and inflammatory reactions than males—differences that are inherent, sex steroid–mediated, or both and possibly the evolutionary products of natural selection of female and male roles.