Ca2+-induced Ca2+ release (CICR) from intracellular stores amplifies the Ca2+ signal that results from depolarization. In neurons, the amplification has been described as a graded process. Here we show that regenerative CICR develops as an all-or-none event in cultured rat dorsal root ganglion neurons in which ryanodine receptors have been sensitized to Ca2+ by caffeine. We used indo-1-based microfluorimetry in combination with whole-cell patch-clamp recording to characterize the relationship between Ca2+ influx and Ca2+ release. Regenerative release of Ca2+ was triggered when action potential-induced Ca2+ influx increased the intracellular Ca2+ concentration ([Ca2+]i) above threshold. The threshold was modulated by caffeine and intraluminal Ca2+. A relative refractory period followed CICR. The pharmacological profile of the response was consistent with Ca2+ influx through voltage-gated Ca2+ channels triggering release from ryanodine-sensitive stores. The activation of a suprathreshold response increased more than fivefold the amplitude and duration of the [Ca2+]i transient. The switch to a suprathreshold response was regulated very precisely in that addition of a single action potential to the stimulus train was sufficient for this transformation. Confocal imaging experiments showed that CICR facilitated propagation of the Ca2+ signal from the plasmalemma to the nucleus. This all-or-none reaction may serve as a switch that determines whether a given electrical signal will be transduced into a local or widespread increase in [Ca2+]i.