Infusion of GRP into conscious sheep and dogs produced elevations of systemic plasma levels of insulin, glucagon, and pancreatic polypeptide (PP). In the dog, infusions of GRP produced dose-dependent decreases in plasma glucose levels, whereas, in the sheep, dose-dependent increases in plasma glucose levels occurred. Glucose turnover studies demonstrated that infusions of GRP produce prompt increases in the rate of appearance of glucose in sheep, but previous studies demonstrated a transient decrease in the rate of appearance of glucose in dogs, suggesting that sheep and dogs differ in hepatic responses to the elevated levels of insulin and glucagon. GRP was a potent PP secretagogue in the sheep, whereas, in contrast to results in the dog, infusions of GRP did not result in elevations of plasma levels of gastrin in sheep. GRP has multiple complex stimulatory effects on the endocrine pancreas, and there exist species-dependent differences in responses, which affect the potency and spectrum of the hormone-releasing activity of GRP. Further studies are required to determine the precise anatomical relation of GRP-containing nerve fibers to islet cells and to elucidate the pathways by which GRP activates endocrine pancreatic hormone release.