Glucagon-Like Peptide-1 receptor agonists (GLP-1RAs) have a broadly applicable biology and are approved for the treatment of diabetes as well as obesity. Physiologically, GLP-1 is short-acting, and a key element to treatment success is that pharmacological agents are long-acting. Liraglutide and semaglutide are fatty acid acylated long-acting GLP-1RAs that bind to serum albumin non-covalently via the fatty acid binding sites, and thereby have pharmacokinetic profiles which last for 24 hours/day. Liraglutide has been approved for the treatment of obesity since 2014, and recently also received a paediatric indication, whereas semaglutide has completed phase 3 clinical studies. Semaglutide has been documented to lead to significantly greater weight loss compared to other GLP-1RAs. GLP-1R expression in the pancreas and brain accounts for the respective improvements in glycemic control and body weight. Mechanistically, GLP-1RAs lower body weight through an effect to reduce energy intake. There is a reduction in feelings of hunger, increases in satiety and effects on the reward system resulting in reduced craving for food and improved food choices. Neural GLP-1Rs are the main targets for the weight loss mechanism. Whole brain imaging studies in rodents show that peripherally-administered GLP-1RAs have access to select sites in the brain, and also communicate to the brain through the circumventricular organs, of which many have GLP-1Rs. These agents do not cross the blood brain barrier passively, and their brain accumulation is dependent on presence of GLP-1R. New data show that there are differences in the brain distribution of semaglutide compared to liraglutide. Both molecules also positively affect cardiovascular (CV) outcomes in individuals with type 2 diabetes, and an outcome study in obesity in ongoing. This ongoing study recruits 17,500 patients with obesity and is an event driven trial. In conclusion, the GLP-1 biology shows potential in obesity and semaglutide is undergoing testing for an effect to lower cardiovascular risk also in patients with obesity.