Local anesthetics (LAs) are chemicals that reversibly block nerve pathways after regional administration. Despite their long clinical use, the electrophysiologic basis of LA action on nerve has been established only in the past 20 years. Recent studies have refined our understanding of LA mechanisms through measurements of Na+ channel gating currents, single-channel recordings, and clarification of competitive antagonism between LAs and activator drugs. This review discusses the electrophysiology and biochemistry of Na+ channels, recent discoveries about LA mechanisms, and four key questions: 1) What microscopic events regulate ion permeability changes in nerve impulses? 2) What is the structure of the Na+ channel? 3) Where and how do LAs bind to the Na+ channel? 4) What are the fundamental microphysiological actions of LAs? The review also speculates whether inhibition of Na+ currents is the sole mechanism by which LA produces spinal or epidural anesthesia. Excitable cells use ionic disequilibria across semipermeable membranes to generate impulse conduction. In nerve cells, the Na+–K+ ATPase maintains the resting membrane potential. During an action potential, voltage-gated Na+ channels open briefly, allowing Na+ ions to flow into the cell, depolarizing the membrane. Sodium channels close spontaneously, limiting the duration of the depolarizing current. A more slowly developing outward current, often of K+ ions, helps repolarize the membrane. Local ionic currents propagate the depolarization wave. Electrophysiologic techniques such as extracellular measurement of action potentials, voltage clamp, gating currents, and single-channel observations by patch clamp have been used to study LA actions. Voltage clamp allows quantitative analysis of specific ion conductances and anesthetic actions. Gating currents, associated with channel transitions between conducting and nonconducting forms, can be measured under certain conditions. Single-channel observations reveal the conductance, ionic selectivity, and gating behavior of ion channels. Tonic and phasic LA actions inhibit Na+ channels, reducing the aggregate inward sodium current. Tonic inhibition occurs during infrequent stimulation, while phasic inhibition results from increased depolarization frequency. These mechanisms may arise from differences in LA binding kinetics at a single site or binding to separate sites. Three general mechanisms of channel inhibition are discussed: open channel block, activation process inhibition, and inactivation process inhibition. The structure of the Na+ channel includes large hydrophobic regions, possibly in α-helical conformations, interspersed with hydrophilic regions. Sodium channels have a major glycoprotein with a molecular weight of roughly 200,000, and varying numbers of other subunits. The Na+ channel is oriented with its glycosylated groups on the outside surface of the cellular membrane. The binding site of LAs on Na+ channels is not directly identified, but indirect evidence suggests it is located inLocal anesthetics (LAs) are chemicals that reversibly block nerve pathways after regional administration. Despite their long clinical use, the electrophysiologic basis of LA action on nerve has been established only in the past 20 years. Recent studies have refined our understanding of LA mechanisms through measurements of Na+ channel gating currents, single-channel recordings, and clarification of competitive antagonism between LAs and activator drugs. This review discusses the electrophysiology and biochemistry of Na+ channels, recent discoveries about LA mechanisms, and four key questions: 1) What microscopic events regulate ion permeability changes in nerve impulses? 2) What is the structure of the Na+ channel? 3) Where and how do LAs bind to the Na+ channel? 4) What are the fundamental microphysiological actions of LAs? The review also speculates whether inhibition of Na+ currents is the sole mechanism by which LA produces spinal or epidural anesthesia. Excitable cells use ionic disequilibria across semipermeable membranes to generate impulse conduction. In nerve cells, the Na+–K+ ATPase maintains the resting membrane potential. During an action potential, voltage-gated Na+ channels open briefly, allowing Na+ ions to flow into the cell, depolarizing the membrane. Sodium channels close spontaneously, limiting the duration of the depolarizing current. A more slowly developing outward current, often of K+ ions, helps repolarize the membrane. Local ionic currents propagate the depolarization wave. Electrophysiologic techniques such as extracellular measurement of action potentials, voltage clamp, gating currents, and single-channel observations by patch clamp have been used to study LA actions. Voltage clamp allows quantitative analysis of specific ion conductances and anesthetic actions. Gating currents, associated with channel transitions between conducting and nonconducting forms, can be measured under certain conditions. Single-channel observations reveal the conductance, ionic selectivity, and gating behavior of ion channels. Tonic and phasic LA actions inhibit Na+ channels, reducing the aggregate inward sodium current. Tonic inhibition occurs during infrequent stimulation, while phasic inhibition results from increased depolarization frequency. These mechanisms may arise from differences in LA binding kinetics at a single site or binding to separate sites. Three general mechanisms of channel inhibition are discussed: open channel block, activation process inhibition, and inactivation process inhibition. The structure of the Na+ channel includes large hydrophobic regions, possibly in α-helical conformations, interspersed with hydrophilic regions. Sodium channels have a major glycoprotein with a molecular weight of roughly 200,000, and varying numbers of other subunits. The Na+ channel is oriented with its glycosylated groups on the outside surface of the cellular membrane. The binding site of LAs on Na+ channels is not directly identified, but indirect evidence suggests it is located in