Aldosterone, at a concentration of 10(-8)mol/1, increases the short-circuit current (scc, a measure of active sodium transport) across the skin of the frog (Rana pipiens). The other natural amphibian corticosteroid hormone, corticosterone, is about 100 times less potent. The structure-activity relationships of a number of corticosteroids were studied with respect to this response. An 11 beta-hydroxyl group was essential, whereas unsaturation at the C-1 to C-2 positions abolished activity. A 17-hydroxyl group did not enhance the response. Fluorination at the 9 alpha-position increased the affinity of the steroid for the receptor. Synthetic corticosteroids which have a high ratio of glucocorticoid : mineralocorticoid action can increase the scc and one of these, dexamethasone, was even more potent than aldosterone. A methyl group at C-16 appeared to be an important constituent for this response but it had to be in the alpha-position. The effects of both aldosterone and dexamethasone were inhibited by spironolactone. The results are discussed in relation to the nature of the response and to corticosteroid receptors in the skin of amphibians.