To determine whether volatile fatty acids (VFA) are involved in the regulation of plasma concentrations of insulin of glucagon in the goat, VFA, separately or in combination, were administered into the jugular vein, the portal vein or the rumen, and their effect on pancreatic hormones as well as on VFA measured in venous blood. Propionate, n-butyrate and n-valerate, but not acetate, injected in pharmacological doses, were potent stimuli not only of the secretion into the plasma of insulin but also of glucagon. As regards insulin, the response to VFA was probably not mediated to an appreciable extent by glucose or glucagon. Beta-Hydroxybutyrate did not mediate the effect of n-butyrate on insulin and glucagon. The effects of VFA appear to be peculiar to the ruminant since in the rat injection of similar doses resulted in either no changes or very small changes of plasma insulin and glucagon. Intraportal infusions over 4h of mixtures of VFA, resulting in less extreme, more physiological blood concentration of VFA, elicited sudden transient increases in insulin and to a lesser extent in glucagon. After these peaks insulin and glucagon declined to preinfusion levels and remained virtually unaltered during the remainder of the infusion in spite of sustained, raised concentrations of VFA in the peripheral circulation. These results suggest that under these conditions the rate of increase of VFA is a signal for the secretion of pancreatic hormones. Intraruminal infusions, representing a more physiological route of administration, of single VFA at high rates resulted in a small increase in insulin for propionate infusion only, whereas a mixture of VFA at a physiological rate induced barely any change in insulin or glucagon. It is concluded that under physiological conditions the rate of increase of VFA may contribute to the insulin secretion in the free-feeding goat, but it is unlikely that VFA are the sole controlling agents of insulin release. It is even less probable that the release of glucagon is governed by VFA in the free-feeding goat.