1. 1. The activities of key gluconeogenic enzymes have been investigated in the liver and the kidney of the sheep following physiological perturbations. 2. 2. When sheep were fasted, the activities of glucose-6-phosphatase, fructose-1,6-diphosphatase and pyruvate carboxylase increased in both the liver and the kidney. No increase occurred in the activity of phosphoenolpyruvate carboxykinase either in a normal fasted sheep or in a sheep fasted in the later stages of pregnancy. 3. 3. When the levels and the changes in enzymic activities in the sheep are compared with those obtained with rats, it is obvious that major differences in metabolism exist between the two species. 4. 4. Further studies with sheep showed that neither glucocorticoids nor phlorhizin treatment led to an increase in phosphoenolpyruvate carboxykinase in liver. 5. 5. In diabetes, both pyruvate carboxylase and phosphoenolpyruvate carboxykinase were elevated in the liver with no change occurring in the kidney. 6. 6. Possible explanations for these findings are discussed. © 1969.