Hyperglycemia, caused in part by elevated hepatic glucose production (GP), is a hallmark feature of diabetes and obesity. The hypothalamus responds to hormones and nutrients to regulate hepatic GP and glucose homeostasis. This invited perspective focuses on the molecular signaling and biochemical pathways involved in the gluco-regulatory action of hypothalamic glucagon signaling and lipid sensing in health and disease. Recent evidence generated via genetic, molecular and chemical experimental approaches indicates that glucagon and lipid signaling independently trigger complementary hypothalamic mechanisms to lower GP. Thus, targeting hypothalamic glucagon or lipid signaling may have therapeutic potential in diabetes and obesity.