Glucagon, a hormone secreted from the -cells of the endocrine pancreas, is critical for blood glucose homeostasis. It is the major counterpart to insulin and is released during hypoglycemia to induce hepatic glucose output. The control of glucagon secretion is multifactorial and involves direct effects of nutrients on -cell stimulus-secretion coupling as well as paracrine regulation by insulin and zinc as well as other factors secreted from neighboring - and -cells within the islet of Langerhans. Glucagon secretion is also regulated by circulating hormones and the autonomic nervous system. In this review, we describe the components of the -cell stimulus secretion coupling and how nutrient metabolism in the -cell leads to changes in glucagon secretion. The islet cell composition and organization are described in different species and serve as a basis for understanding how the numerous paracrine, hormonal and nervous signals fine-tune glucagon secretion under different physiological conditions. We also highlight the pathophysiology of the -cell and how hyperglucagonemia represents an important component of the metabolic abnormalities associated with diabetes mellitus. Therapeutic inhibition of glucagon action in patients with type 2 diabetes remains an exciting prospect.