Electrical signals are critical for rapid response to long-distance stimuli in animals. Voltage-gated sodium (Nav) channels are responsible for the generation and propagation of action potentials in neurons and muscles. More than 1,000 mutations have been identified in the nine subtypes of human Nav channels, Nav1.1-1.9, that are associated with a variety of disorders, such as epilepsy, arrhythmia, autism spectrum disorder, and pain. Nav1.7, a subtype that is well-established to be directly associated with pain syndromes, including both extreme pain disorders and insensitivity to pain, is widely pursued as a target for the development of novel pain killers. Nav channels are subject to modulation by various toxins, which may be used as the prototype for discovery of novel analgesics. We aim to unveil the structural basis for the specific recognition and mode of action of various toxins on Nav1.7 and establish the foundation for structure-guided drug development for pain relief.