Despite intense research over the last 35 yr, the molecular mechanisms whereby glucose and other major nutrients modulate the -cell stimulus secretion coupling remain an enigma. Advances have been made in understanding how plasma membrane ion channel activity modulates -cell electrical activity and consequently glucagon release. Furthermore, accumulating evidence suggests that a complex network of interacting paracrine, hormonal, and neuronal signaling pathways modulate glucagon secretion. Important species differences in the -cell stimulus secretion coupling as well as in the relative importance of the different components of the signaling networks have significantly hampered our ability to propose a unifying hypothesis for regulation of glucagon secretion. However, accumulating evidence suggests that intraislet insulin and zinc play prominent roles for regulating glucagon release in response to hypoglycemia. A direct inhibitory action of glucose on -cell secretion seems to be of little physiological significance and at least for the rat -cell glucose has a direct stimulatory action on glucagon secretion via mechanisms reminiscent of those described for the ß-cell. Emerging evidence suggests a central role of glucose-sensing neurons in the VMH for the integration and control of whole body glucose homeostasis. However, the relative importance of peripheral vs. central control of glucagon secretion in the regulation of glucose homeostasis remains elusive. With the increased availability of human islets, it will be thrilling to investigate the stimulus secretion events in human -cells. Special focus should be devoted to understanding how glucose inhibits glucagon secretion because evidence suggests that -cell dysfunction associated with diabetes progression is principally a defect in the ability of glucose to suppress glucagon secretion. Therefore, defective signaling rather than a change in -cell mass must be involved (428, 429, 430). This could result from alterations in the paracrine, hormonal, or nervous signaling networks involved in glucose sensing. It is likely that the -cell dysfunction results from a combination of multiple factors, genetic as well as environmental, which will clearly complicate the investigations. Three decades ago Unger and Orci (431) proposed the “bihormonal hypothesis” to explain the origin of hyperglycemia. The model takes into account that in addition to relative or absolute hypoinsulinemia, hyperglucagonemia is essential in the pathogenesis of type 2 diabetes. Since then, additional and important evidence has accumulated implicating hyperglucagonemia in the development of type 2 diabetes. This has prompted major investments in the development of potential drug candidates antagonizing glucagon action. A better understanding of the -cell (patho)physiology in the disease progression will aid the identification of new and better drug targets and therapies. However, it is important to emphasize that although the therapeutic potential of antagonism of glucagon in the treatment of diabetes is likely to be highly beneficial, it will not be a cure.