The effects of cortisol on hepatic and renal gluconeogenic enzyme activities were investigated in sheep fetuses during late gestation and after experimental manipulation of plasma cortisol levels by fetal adrenalectomy and exogenous infusion of cortisol. Hepatic and renal gluconeogenic enzyme activities increased with increasing gestational age in parallel with the normal rise in fetal cortisol levels towards term (146 +/- 2 days). For the majority of enzymes this increase in activity towards term was prevented when the prepartum cortisol surge was abolished by fetal adrenalectomy and stimulated prematurely in fetuses younger than 130 days by exogenous infusion of cortisol. When the data from all the fetuses were combined irrespective of treatment or gestational age, there were significant positive correlations between the log plasma cortisol concentration in utero and the activities of glucose-6-phosphatase, fructose diphosphatase, phosphoenolpyruvate carboxykinase and aspartate transaminase in the fetal liver and kidney, and pyruvate carboxylase in the fetal liver but not in the kidney. No correlation was observed between log plasma cortisol and alanine aminotransferase activity in either fetal liver or kidney. These findings show that cortisol is a physiological regulator of most of the fetal gluconeogenic enzymes and enhances the glucogenic capacity of the sheep fetus during late gestation.