Voltage-gated Na+ channels initiate action potentials in excitable cells and are important targets for drugs. Recent research gives new insight into the structural basis for permeation, drug-block, and voltage-dependent gating. Voltage-sensing depends on the S4 segments, which move outward through a gating pore via a ‘sliding-helix’ mechanism. Outward movement of S4 is coupled to pore-opening by tilting and rotation of the S6 segments. A structural model reveals conformational changes underlying activation and pore-opening, and disulfide locking of substituted cysteines demonstrates voltage-dependent formation of ion pairs during channel activation, as in the sliding-helix model. Na+ channel blocking drugs bind to a conserved receptor site in the inner pore, and binding is enhanced by repetitive opening of the pore and inactivation of the channel. A three-dimensional view of these structural components is provided by a high-resolution structure of a voltage-gated Na+ channel from Arcobacter butzleri (NavAb) captured in a closed-pore conformation with four activated voltage-sensors at 2.7 Å resolution. The arginine gating charges make multiple hydrophilic interactions within the voltage-sensor, including unanticipated hydrogen bonds to the protein backbone.  Comparisons to previous open-pore K+ channel structures suggest that the voltage-sensor domains and the S4-S5 linkers dilate the central pore by pivoting around a hinge at the base of the pore.  The NavAb selectivity filter is short, ~4.6 Å wide, and water-filled, with four acidic glutamate side-chains surrounding the narrowest part of the ion-conduction pathway. This unique structure presents a high-field-strength anionic coordination site, which confers Na+ selectivity through partial dehydration via direct interaction with glutamate side-chains.  Fenestrations in the sides of the pore are unexpectedly penetrated by fatty-acyl chains that extend into the central cavity, and these portals are large enough for entry of small, hydrophobic pore-blocking drugs. Determination of the crystal structure of NavAb in two similar inactivated states suggests asymmetric pore collapse as the mechanism of slow inactivation of NavAb channels and reveals dramatic conformational change in its drug receptor site.