Epidemiological evidence suggests that an adverse fetal environment permanently ‘programmes’ physiology leading to increased risks of cardiovascular, metabolic, neuroendocrine and psychiatric disorders in adulthood. In a variety of animal models, prenatal stress, glucocorticoid exposure or inhibition/knockout of 11β-hydroxysteroid dehydrogenase type 2 (11β-HSD2), the feto-placental ‘barrier’ to maternal glucocorticoids, reduces birth weight and causes permanent hypertension, hyperglycaemia, increased hypothalamic-pituitary-adrenal (HPA) axis activity and anxiety-related behaviours in the adult offspring. In humans, 11β-HSD2 gene mutations lower birth weight and placental 11β-HSD2 activity correlates directly with birth weight and inversely with infant blood pressure. Low birth weight babies have higher plasma cortisol levels throughout adult life, indicating HPA programming. Maternal glucocorticoid therapy alters offspring cognition and affect. Pregnant women exposed to the World Trade Centre atrocity appeared to transmit the neuroendocrine change to their 1-year-old offspring, predominantly if exposed in the third trimester. The molecular mechanisms may reflect permanent changes in the expression of specific transcription factors, perhaps key is the glucocorticoid receptor (GR) itself. Differential programming of GR in different tissues, including hippocampus and amygdala, reflects effects upon one or more of the multiple tissue-specific alternate first exons/promoters of the GR gene. There are exquisitely targeted promoter-specific, and indeed transcription-factor binding site-specific, changes in DNA methylation that occur only during specfic sensitive periods of development. Curiously, some of these effects appear to be ‘inherited’ transgenerationally, affecting a further generation, itself unexposed to exogenous glucocorticoids at any point in the lifespan. Such effects can follow the male line, indicating epigenetic changes that persist through meiosis, fertilization and embryogenesis. Thus developmental exposure to excess glucocorticoids ‘programmes’ peripheral and CNS functions in adult life that may predispose to pathology and these effects may be transmitted into one or perhaps more subsequent generations.