Normal young male Wistar rats were given daily subcutaneous depot doses of estrogens for periods from 1 to 15 days. After starving for about 20 hours, the animals were decapitated and samples of liver taken for total lipid and glycogen determinations. The diaphragms were excised, incubated in vitro with glucose alone or with glucose plus insulin. Glucose uptake and glycogen deposition were measured. The adrenals were also incubated in vitro and the gluco-corticoid output measured. The estrogenic compounds given in vivo were found to increase the in vitro response of diaphragm muscle. For example, the administration of ethinyl estradiol for 12 days increased the glucose utilization and glycogen formation in diaphragm by as much as 60% compared to controls. The insulin effect on glucose uptake (increase of stimulated over unstimulated) in diaphragms from ethinyl estradiol treated animals was often increased 2-3 times. The insulin effect on glycogen deposition was also increased but to a lesser extent. Estradiol and stilbestrol were less effective than ethinyl estradiol in increasing the insulin effect. Liver glycogen levels were higher and liver total lipid levels slightly lower in the estrogen treated rats. The secretion of corticoids in vitro was significantly lower in adrenals from estrogen treated rats. The lowest output was found in adrenals from the ethinyl estradiol treated animals. The concentration of corticoids remaining after incubation was also found to be lower in the adrenal tissues of estrogen treated rats. A mechanism of action is postulated for the insulin potentiating effect of estrogens.