Salt sensitivity of blood pressure is a major risk factor for cardiovascular morbidity and chronic renal disease. The underlying mechanisms are unclear but sub-clinical renal impairment and corticosteroid excess may be involved. Both cortisol (corticosterone in rodents) and aldosterone exert major influences on renal function and blood pressure. Although the pathways controlling glucocorticoid and mineralocorticoid activity are classically held to be independent, we have found areas of commonality in the cardiovascular/renal phenotypes of “glucocorticoid” and “mineralocorticoid” hypertension. In ACTH excess, for example, glucocorticoids cause salt-sensitive hypertension and electrolyte abnormalities usually associated with high levels of mineralocorticoid (1). In this setting, corticosteroid cross-talk involves activation of both the mineralocorticoid receptor (MR) and glucocorticoid receptor (GR) by corticosterone (2). In vivo, MR is protected from glucocorticoid activation by 11β-hydroxysteroid dehydrogenase type 2 (11βHSD2). Inactivating mutations in the encoding gene (HSD11B2) remove this protection and cause the severe disorder of Apparent Mineralocorticoid Excess(3) (Mullins). In a mouse model of this disease, the epithelial sodium channel (ENaC) is activated, despite vanishing low levels of aldosterone(4). Null mutations are rare but polymorphisms in HSD11B2 have been associated with salt-sensitivity of blood pressure in normotensive individuals(5) and are likely to be clinically significant. We have used mice heterozygote for a null mutation in Hsd11b2 (Hsd11b2+/-) to explore the link between reduced enzyme activity and salt sensitivity of blood pressure. Feeding a high sodium diet to Hsd11b2+/- mice caused a sustained increase in blood pressure, sodium retention and potassium depletion. These classical symptoms of mineralocorticoid excess were not prevented by MR antagonism, as anticipated, but by GR blockade. Hsd11b2+/- mice were able to down-regulate aldosterone production in response to high dietary sodium but corticosterone production was significantly enhanced. These results illustrate the complexity of corticosteroid cross-talk and identify a new role for 11βHSD2 to regulate the activity of the hypothalamic-pituitary-adrenal axis. The mechanisms causing salt sensitivity are not yet clear. The use of inter-related models of corticosteroid excess to identify common phenotypes will be informative. Inappropriate regulation of ENaC may be involved. Our recent data link this to a reduction in blood flow to the renal medulla, which would have detrimental consequences for tissue oxygenation.