Four decades of glucagon research have firmly established its hormonal status and physiologic roles in normal glucose homeostasis and its pathogenic roles in diabetes. It now seems that the “glucagonocentric hypothesis” of diabetes has surpassed the “insulinocentrichypothesis” of diabetes established in the first half of the 19th century. What is obvious is that the morphologic, physiologic, and clinical findings spanning these last years point to the vital but underappreciated paracrine action of insulin on juxtaposed α-cells. Future studies in normal and diabetic human subjects should identify the extent to which reduction of Gcgr signaling coupled or not to insulin therapy produces a compelling therapeutic benefit without incurring a risk of adverse events (Lefebvre, Lecture).