The proglucagon-derived peptides glucagon-like peptide-1 (GLP-1) and glucagon-like peptide-2 (GLP-2) are released from gut endocrine cells in response to nutrient ingestion, and regulate gastric acid secretion, gastrointestinal motility, nutrient absorption, glucose homeostasis and cell proliferation and survival. GLP-1 and GLP-2 are also synthesized in the central nervous system, predominantly in neurons of the nucleus of the solitary tract in the brainstem, and to a lesser extent in the hypothalamus. Intracerebroventricular (ICV) administration of GLP-1 inhibits food intake in rodents and ICV GLP-1 activates neuroendocrine circuits, the sympathetic nervous system, and pathways coupled to transduction of an interoceptive stress response. Interruption of GLP-1R signaling in the rodent brain attenuates the development of a conditioned taste response and fos-activation following exposure to noxious agents such as lithium chloride. Although peripheral administration of GLP-1 to human subjects is associated with inhibition of gastric emptying, feelings of satiety, and reduction of food intake, chronic treatment of diabetic subjects with GLP-1R agonists prevents weight gain, but is not associated with major weight loss over 8-12 week treatment periods. Although ICV injection of GLP-2 also inhibits food intake, GLP-2 is much less anorexic compared to GLP-1. Both GLP-1 and GLP-2 exert direct cytoprotective and regenerative actions, suggesting that activation of glucagon-like peptide receptor signaling may attenuate cellular injury in the CNS. As peripheral administration of GLP-1R agonists activate CNS GLP-1R systems, the biology of glucagon-like peptides in the brain is directly relevant to pharmaceutical use of glucagon-like peptide agonists for the treatment of human disease.