Pancreatic adaptation represents dietary regulation of gene expression; dietary substrates alter the synthesis and mRNA levels of their respective digestive enzymes. The mechanisms whereby mRNA levels change are not understood, but they must be elucidated. Although the changes in synthesis of proteases, amylase, and lipase parallel the changes in their mRNA levels in response to respective substrates, the concomitant changes in the synthesis of the other enzymes can be discordant with mRNA levels. The evidence supports a pretranslational mechanism of the adaptation of proteases, amylase, and lipase to their respective substrates and suggests potential translational mechanisms of other enzymes in these adaptations. Changes in synthesis occur within hours after a dietary change, but whether mRNA levels also change so early is unknown. Rapid, adaptive changes may occur by a different mechanism from later adaptation, possibly by translational control or nuclear transport. The differential effects of acute and chronic caerulein administration support the possibility of multiple mechanisms of regulation by a single effector. The mediators of pancreatic adaptations have not yet been identified, except for adaptation to dietary protein. CCK appears to mediate protease adaptation through the feedback regulation of its release by dietary protein. Available evidence supports a role of insulin and glucose in the adaptation to carbohydrate and a role of secretin and ketones in the adaptation to dietary fat. Elucidation of the mediators of pancreatic adaptation to carbohydrate and fat and their mechanisms is needed.