The insulin secretory response to a meal results largely from glucose stimulation of the pancreatic islets and both direct and indirect (autonomic) glucose-dependent stimulation by incretin hormones released from the gastrointestinal tract. Two incretins, Glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like peptide-1 (GLP-1), have so far been identified. Localization of the cognate G protein-coupled receptors for GIP and GLP-1 revealed that they are present in numerous tissues in addition to the endocrine pancreas, including the gastrointestinal, cardiovascular, central nervous and autonomic nervous systems (ANSs), adipose tissue, and bone. At these sites, the incretin hormones exert a range of pleiotropic effects, many of which contribute to the integration of processes involved in the regulation of food intake, and nutrient and mineral processing and storage. From detailed studies at the cellular and molecular level, it is also evident that both incretin hormones act via multiple signal transduction pathways that regulate both acute and long-term cell function. Here, we provide an overview of current knowledge relating to the physiological roles of GIP and GLP-1, with specific emphasis on their modes of action on islet hormone secretion, β-cell proliferation and survival, central and autonomic neuronal function, gastrointestinal motility, and glucose and lipid metabolism. However, it is emphasized that despite intensive research on the various body systems, in many cases there is uncertainty as to the pathways by which the incretins mediate their pleiotropic effects and only a rudimentary understanding of the underlying cellular mechanisms involved, and these are challenges for the future.