Mineralocorticoid receptors in distal nephron have no intrinsic specificity for mineralocorticoids over glucocorticoids, but they are protected from glucocorticoids (ie, cortisol in humans, corticosterone in rats) by the enzyme 11 β-hydroxysteroid dehydrogenase (11β-HSD), which inactivates these steroids to cortisone and 11-dehydrocorticosterone, respectively. Recent work has demonstrated that the enzyme is expressed as multiple tissue-specific isoforms, some of which catalyze the conversion of cortisone to cortisol. These may allow 11β-HSD to modulate access of ligands to glucocorticoid as well as mineralocorticoid receptors, and to amplify as well as attenuate tissue responses. Protection of mineralocorticoid receptors fails in congenital 11β-HSD deficiency and after inhibition of the enzyme by licorice or carbenoxolone. In these circumstances, cortisol-dependent mineralocorticoid excess and hypertension ensue. Recent studies illustrate that similar deficiencies of 11β-dehydrogenase activity may contribute to pathophysiology in ectopic corticotropin syndrome and essential hypertension. This novel mechanism of hypertension may therefore have an impact on everyday clinical practice.