The tremendous therapeutic potential of voltage-gated sodium channels (Na_vs) has been the subject of many studies in the past and is of intense interest today. Na_v1.7 channels in particular have received much attention recently because of strong genetic validation of their involvement in nociception. Here we summarize the current status of research in the Na_v field and present the most relevant recent developments with respect to the molecular structure, general physiology, and pharmacology of distinct Na_v channel subtypes. We discuss Na_v channel ligands such as small molecules, toxins isolated from animal venoms, and the recently identified Na_v1.7-selective antibody. Furthermore, we review eight characterized ligand binding sites on the Na_v channel α subunit. Finally, we examine possible therapeutic applications of Na_v ligands and provide an update on current clinical studies.