The peripheral and central glucagon-like-peptide-1 (GLP-1) systems play an essential role in glycemic and energy balance regulation. Thus, pharmacological targeting of peripheral and/or central GLP-1 receptors (GLP-1R) may represent a potential long-term treatment option for both obesity and type-II diabetes mellitus (T2DM). Uncovering and understanding the neural pathways, physiological mechanisms, specific GLP-1R populations, and intracellular signaling cascades that mediate the food intake inhibitory and incretin effects produced by GLP-1R activation are vital to the development of these potential successful therapeutics. Particular focus will be given to the essential role of the nucleus tractus solitarius (NTS) in the caudal brainstem, as well as the gut-to-brain communication by vagal afferent fibers in mediating the physiological and behavioral responses following GLP-1R activation. The paper represents an invited review by a symposium, award winner or keynote speaker at the Society for the Study of Ingestive Behavior [SSIB] Annual Meeting in Portland, July 2009.