Human self-reports of stress during pregnancy are associated with increased circulating cortisol, but only 10–20% of maternal cortisol passes to the fetus. This barrier function of the placenta is achieved through the actions of the enzyme 11b-hydroxysteroid dehydrogenase type 2, which converts the glucocorticoids cortisol/corticosterone into the inactive metabolites cortisone/11b-dehydrocorticosterone, thus preventing the activation of glucocorticoid receptors. In contrast, the enzyme 11ß–HSD1 converts inactive glucocorticoids to cortisol/corticosterone. Targeted gene deletion and pharmacological studies suggest a functional consequence of 11ß–HSD for the development of the hypothalamicpituitary adrenal response to stress. In mice, mutation of the HSD11B2 gene leads to hypertension, excess mineralocorticoid activity, and increased anxiety-like behavior in adulthood whereas HSD11B1 mutation leads to attenuated negative-feedback of the HPA response to stress and improved cognitive performance in aging. Pharmacological inhibition of 11ß–HSD2 during pregnancy or administration of dexamethasone, a synthetic glucocorticoid that is not metabolized by 11ß–HSD2, leads to molecular and neurobiological changes within the HPA axis associated with increased stress responsivity and anxiety-like behavior in adulthood. These glucocorticoid programming effects may also be evident in humans, consequent to prenatal betamethasone exposure or inhibition of 11ß–HSD2 through elevated glycyrrhizin consumption during pregnancy. These studies suggest that the regulation of placental 11ß–HSD2 levels may be a mechanistic link between the experience of maternal gestational stress and long-term health outcomes in offspring. There is increasing evidence that maternal adversity during pregnancy may lead to a down-regulation of 11ß–HSD2. In rats, chronic restraint stress during gestational days 11–20 was found to decrease placental 11ß–HSD2 enzymatic activity and decrease mRNA levels of this gene. Similarly, rat dams that are food restricted from gestational days 10–20, a manipulation that increases maternal plasma corticosterone and induces similar phenotypes to those observed following prenatal stress, have reduced placental protein levels of 11ß–HSD2. In humans, Nutlin-3 heightened maternal anxiety was found to be negatively correlated with placental HSD11B2 mRNA levels. Reduced placental HSD11B2 mRNA levels have also been found associated with intrauterine growth retardation and pre-term birth, suggesting that the transcriptional activity of this enzyme may be predicted by maternal adversity and predictive of high risk birth outcomes. Regulation of gene expression through epigenetic mechanisms – factors that alter gene transcription without altering DNA sequence – is being increasingly explored within the context of environmentally-induced changes in neurobiology, metabolism, and disease risk.