The prevalence of the obesity and diabetes epidemic has triggered tremendous research investigating the role of the central nervous system (CNS) in the regulation of food intake, body weight gain and glucose homeostasis. This invited review focuses on the role of two pancreatic hormones--insulin and glucagon--that trigger signaling pathways in the brain to regulate energy and glucose homeostasis. Unlike in the periphery, insulin and glucagon signaling in the CNS does not seem to have opposing metabolic effects, as both hormones exert a suppressive effect on food intake and weight gain. They signal through different pathways and alter different neuronal populations suggesting a complementary action of the two hormones in regulating feeding behavior. Similar to its systemic effect, insulin signaling in the brain lowers glucose production. However, the ability of glucagon signaling in the brain to regulate glucose production remains unknown. Future studies that aim to dissect insulin and glucagon signaling in the CNS that regulate energy and glucose homeostasis could unveil novel signaling molecules to lower body weight and glucose levels in obesity and diabetes.