Voltage-gated sodium (Nav) channels are responsible for the initiation of electrical signaling. Being associated with a variety of disorders, Nav channels are targeted by many pharmaceutical drugs and natural toxins. We have determined the cryo-EM structures of human Nav1.1-Nav1.8, alone or in complex with distinct auxiliary subunits, toxins, and drugs. These high-resolution structures not only afford unprecedented insights into the working and disease mechanism of these channels, but also reveal novel pharmacological sites. In light of these structural observations, we proposed a structure-based nomenclature for ligand binding sites on Nav channels. Intriguingly, we have observed dual or even triple binding sites for drugs and peptide toxins targeting Nav channels. Advances in the structural pharmacoloy of Nav channels will facilitate rational drug design and optimization.