Voltage-gated sodium channels (VGSCs) play a central role in the generation and propagation of action potentials in neurons and other cells. VGSC modulators have their origins in empirical pharmacology and are being used as local anaesthetics, antiarrhythmics, analgesics and antiepileptics, and for other disorders. However, the identification of a multigene family of VGSCs, along with tools to study the different subtypes in pathophysiology, is now providing a rational basis for selective intervention. Recent advances have addressed the technical challenges of expressing and assaying these complex proteins, enabling the correlation of empirical pharmacology to subtypes and the screening of individual subtypes for novel inhibitors with increased potency and selectivity.