The production of ketone bodies (KB) is dependent on the amount of free fatty acids (FFA) supplied to the liver and on the hepatic metabolic fate of fatty acids and their orientation towards oxidation and ketogenesis or reesterification. In vivo ketogenesis can thus be regulated at the pre-hepatic (lipolysis) or hepatic level. We first investigated the role of FFA availability on the rate of KB production and then the effects of epinephrine, thyroid hormones, insulin and glucagon on the relationship between FFA availability and KB production. An increase in FFA availability augmented KB production not only by a mass effect but also by a diversion of hepatic fatty acid metabolism towards ketogenesis. The ketogenic effect of epinephrine and thyroid hormones depended only on their stimulatory action on lipolysis and FFA availability. An excess of thyroid hormones had no direct effect on hepatic ketogenesis, whereas the direct action of epinephrine on liver was rather anti-ketogenic. Glucagon stimulated hepatic ketogenesis, whereas a short-term increase in insulinemia within the physiological range appeared to have no restrictive action.