We describe three voltage-dependent inward currents in human pancreatic beta-cells. First, a rapidly inactivating Na+ current, blocked by tetrodotoxin (TTX) is seen upon brief depolarization to or beyond -40 mV. Second, a transient, low-voltage-activated (LVA), amiloride-blockable Ca2+ current is seen upon depolarization to or beyond -55 mV; it inactivates within less than 1s of sustained depolarization to -40 mV. Third, a more sustained, high-voltage-activated (HVA) Ca2+ current, which shows variable sensitivity to dihydropyridines is seen upon depolarization to or beyond -40 mV, and thereafter slowly inactivates over a time course of many seconds. Our pharmacological evidence suggests that all three currents contribute to action potential initiation and upstroke when the background membrane potential (Vm) is equal or negative to -45 to -40 mV, a situation often induced by glucose concentrations (5-6 mM) in the range of those seen post-prandially. Consistent with this, TTX drastically reduces both transient and sustained insulin secretion in the presence of 5-6 mM glucose, but has little effect in 10 mM glucose, at which concentration cells rapidly depolarize to approximately -35 mV, a Vm sufficient to rapidly inactivate Na+ and LVA Ca2+ currents.