Mineralocorticoid receptors in the distal nephron have no intrinsic specificity for mineralocorticoids over glucocorticoids (cortisol in humans; corticosterone in rodents), but are protected from glucocorticoids by the enzyme 11β-hydroxysteroid dehydrogenase, 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 catalyse the reverse conversion of cortisone to cortisol. These isoforms may allow 11β-hydroxysteroid dehydrogenase to modulate access of ligands to glucocorticoid and mineralocorticoid receptors, as well as to amplify and attenuate tissue responses. 11β-hydroxysteroid dehydrogenase-mediated protection of mineralocorticoid receptors fails in congenital 11 β-hydroxysteroid dehydrogenase deficiency and after inhibition of the enzyme by liquorice. In these circumstances, cortisol-dependent mineralocorticoid excess and hypertension ensue. Recent studies suggest that similar deficiencies of 11β-dehydrogenase activity may contribute to pathophysiology in common clinical syndromes, illustrating the potential significance of this novel mechanism for development of hypertension.