In this presentation, three facets of the topic will be addressed: signal specificity, receptor specificity and kinetics. First, both clinical and co-transfection studies show cortisol to be a potent mineralocorticoid agonist when it occupies Type I (mineralocorticoid) receptors. Cytosol Type I receptors from various tissues, and recombinant-derived human renal mineralocorticoid receptors, show equivalent affinity in vitro for aldosterone and for cortisol, which circulates at approximately 100-fold higher levels. In vivo, aldosterone specificity of Type I receptors in physiological mineralocorticoid target tissues reflects local metabolism of cortisol (but not of aldosterone), to receptor-inactive cortisone, by the microsomal enzyme 11 beta OH steroid dehydrogenase. Secondly, alpha-lactalbumin synthesis in the mid-pregnant rat mammary gland explant is stimulated by very low doses of glucocorticoids, but progressively inhibited at higher doses, and is exquisitely sensitive to progestin blockade. To reconcile these data, we have developed a model of transcriptional regulation involving multiple overlapping glucocorticoid and progesterone regulatory elements. Finally, in the Porsolt swimming rat model, the effect of adrenalectomy on a learned response is reversed by glucocorticoid administration up to an hour after the conditioning experiment.