Glucose is the primary metabolic fuel in mammalian fetuses, yet mammals are incapable of endogenous glucose production until several hours after birth. Thus, when the maternal supply of glucose ceases at birth there is a transient hypoglycemia that elicits a counterregulatory surge in circulating catecholamines. Because the innervation of adrenomedullary chromaffin cells (AMCs) is immature at birth, we hypothesized that neonatal AMCs act as direct glucosensors, a property that could complement their previously established roles as hypoxia and acid hypercapnia sensors. During perforated-patch, whole cell recordings, low glucose depolarized and/or excited a subpopulation of neonatal AMCs; in addition, aglycemia (0 mM glucose) caused inhibition of outward K+ current, blunted by the simultaneous activation of glibenclamide-sensitive KATP channels. Some cells were excited by each of the three metabolic stimuli, i.e., aglycemia, hypoxia (Po2 ∼30 mmHg), and isohydric hypercapnia (10% CO2; pH = 7.4). Using carbon fiber amperometry, aglycemia and hypoglycemia (3 mM glucose) induced robust catecholamine secretion that was sensitive to nickel (50 μM and 2 mM) and the L-type Ca2+ channel blocker nifedipine (10 μM), suggesting involvement of both T-type and L-type voltage-gated Ca2+ channels. Fura-2 measurements of intracellular Ca2+ ([Ca2+] i) revealed that ∼42% of neonatal AMCs responded to aglycemia with a significant rise in [Ca2+] i. Approximately 40% of these cells responded to hypoxia, whereas ∼25% cells responded to both aglycemia and hypoxia. These data suggest that together with hypoxia and acid hypercapnia, low glucose is another important metabolic stimulus that contributes to the vital asphyxia-induced catecholamine surge from AMCs at birth.