This review article by Butterworth and Strichartz provides an in-depth analysis of the molecular mechanisms underlying the action of local anesthetics (LAs) on sodium (Na⁺) channels. The authors discuss the electrophysiology and biochemistry of Na⁺ channels, highlighting recent discoveries that have refined our understanding of LA mechanisms. Key questions addressed include which microscopic events regulate ion permeability changes, the structure of Na⁺ channels, where and how LAs bind to these channels, and the fundamental microphysiological actions of LAs. The article covers various electrophysiological techniques used to study LAs, such as extracellular measurement of action potentials, voltage clamp, gating currents, and single-channel observations by patch clamp. These techniques help in understanding the mechanisms by which LAs block nerve impulses by inhibiting individual Na⁺ channels and reducing the aggregate inward sodium current. The authors also explore the different modes of LA action, including tonic and phasic inhibition, and the mechanisms by which LAs modify channel gating. They discuss the role of pH in LA action, the structure of Na⁺ channels, and the nature and locus of the LA binding site. The review emphasizes the importance of understanding the interactions between LAs and Na⁺ channels, and the implications of these mechanisms for the clinical use of local anesthetics.This review article by Butterworth and Strichartz provides an in-depth analysis of the molecular mechanisms underlying the action of local anesthetics (LAs) on sodium (Na⁺) channels. The authors discuss the electrophysiology and biochemistry of Na⁺ channels, highlighting recent discoveries that have refined our understanding of LA mechanisms. Key questions addressed include which microscopic events regulate ion permeability changes, the structure of Na⁺ channels, where and how LAs bind to these channels, and the fundamental microphysiological actions of LAs. The article covers various electrophysiological techniques used to study LAs, such as extracellular measurement of action potentials, voltage clamp, gating currents, and single-channel observations by patch clamp. These techniques help in understanding the mechanisms by which LAs block nerve impulses by inhibiting individual Na⁺ channels and reducing the aggregate inward sodium current. The authors also explore the different modes of LA action, including tonic and phasic inhibition, and the mechanisms by which LAs modify channel gating. They discuss the role of pH in LA action, the structure of Na⁺ channels, and the nature and locus of the LA binding site. The review emphasizes the importance of understanding the interactions between LAs and Na⁺ channels, and the implications of these mechanisms for the clinical use of local anesthetics.