Electrical signaling in most nervous systems depends upon sodium current, which flows through voltage-gated sodium channels. From their first voltage clamp measurements, Hodgkin and Huxley (1952) recognized the “dual effect” of voltage on the sodium conductance: In modern terms, depolarization first activates and then inactivates voltage-gated sodium channels, such that current flows only briefly at positive potentials and requires a recovery period at negative potentials before it can flow again upon subsequent depolarization. Both the voltage-dependence and time course of recovery from inactivation set the refractory period for action potential firing. Although tetrodotoxin-sensitive voltage-gated sodium currents show little heterogeneity across neurons, about 25 years ago, we found that cerebellar Purkinje neurons show a qualitatively distinct form of sodium channel gating. There, voltage-gated channels open briefly upon depolarization, permitting transient sodium current to flow, but the same channels reopen to pass a “resurgent” sodium current upon repolarization, indicative of a less stable form of inactivation. This component of sodium current is present in many other neurons typified by rapid or burst firing of action potentials. Changes in resurgent sodium current have been predicted to occur in disorders of excitability, e.g., in association with paroxysmal extreme pain disorder, epilepsy, paramyotonia congenita, long-QT syndrome, and neuropathy. A primary question relevant to the understanding of sodium channel gating, as well as the action potentials that result, is what the mechanisms of resurgent current are, both biophysically and molecularly. In early work, we proposed that sodium channels that generate resurgent current are subject to a rapid, voltage-dependent, open-channel block by an endogenous blocking particle. With depolarization, channels would open and, instead of inactivating in the usual manner, would rapidly become blocked by the native blocker. With repolarization, the blocker would unbind, briefly leaving the pore open to pass resurgent current before channels inactivated normally (at moderately negative potentials) or deactivated (at more negative potentials). Since the time that this mechanism was proposed, many electrophysiological as well as structural results have emerged, which have not only rendered this hypothesis more precise, but also linked it more clearly to research that preceded it. In this talk, I will place the idea of open-channel block as a mechanism for resurgent sodium current in the context of earlier and later studies of ion channel biology and discuss the implications for neural signaling, pathophysiology and drug targeting.