In mammalian systems, the physiological mineralocorticoid is aldosterone (aldo), and the physiological glucocorticoid cortisol (F), or corticosterone (B) in rats and mice. Receptors (MR) with high affinity for aldo, B and F are found in both epithelia and the central nervous system (CNS); receptors (GR) with lower affinity for F and B, and still lower for aldo, are found in essentially all cells. Both MR and GR bind to and activate canonical pentadecamer response elements in transfected cells and in epithelia, wherein MR aldo, B and F all act as agonists. In vivo, in epithelial cells a low Km, NAD-dependent, 11 beta hydroxysteroid dehydrogenase (11 beta OHSD) converts B and F, but not aldo, to receptor-inactive 11-keto congeners, thus allowing aldo to occupy epithelial MR and produce sodium retention. The CNS differs markedly in terms of MR/GR in a number of ways: (i) most but not all MR in the CNS are functionally unprotected, despite the presence of a low Km, NADP-preferring 11 beta OHSD, so that they operate as high-affinity GR; (ii) in such CNS 'MR', aldo antagonizes the effects of B, and vice versa, in contrast with epithelia; (iii) also in contrast with epithelia, activated GR in the CNS do not mimic activated MR, suggesting considerable if not total specificity at the response element level. These differences suggest that glucocorticoids have two distinct domains of action in the CNS, mediated by 'MR' at low B/F concentrations, and GR at higher concentrations; secondly, they suggest that the nuclear recognition and response elements mediating these effects are other than canonical pentadecamer sequences.