Glucagon is known as an important metabolic hormone but has also recently emerged as a efficacious agent in obesity and metabolic disease therapies. However, despite being discovered over 100 years ago, we still don’t understand how it works to regulate metabolism and beyond. During this presentation, I will give an overview about our own and others recent discoveries on how glucagon signals within liver hepatocytes to regulate almost all aspects of metabolism. This new knowledge will have implications on the use, and possible refinement, of glucagon-based therapies for obesity and metabolic diseases.