Voltage-gated sodium channels are dynamic transmembrane proteins that govern action potential initiation and propagation in excitable membranes. Nine mammalian sodium channel isoforms have been identified and functionally expressed thus far. Their amino acid sequences in the transmembrane and extracellular domains are more than 50% identical. Among the nine mammalian sodium channel isoforms, three isoforms - Nav1.7, Nav1.8, and Nav1.9 - are predominantly expressed in the peripheral nervous system and critically contribute to nociception. Mutations of their genes or changes in activity of their (non-mutated) genes give rise to genetic or acquired channelopathies, respectively, that alter nociception. Gain-of-function mutations in the sodium channel Nav1.7 cause erythromelalgia and paroxysmal extreme pain disorder as a result of hyperexcitability of sensory neurons, whereas loss-of-function mutations cause congenital indifference to pain. Peripheral nerve injury may provoke an acquired channelopathy due to altered expression of a set of sodium channel isoforms resulting in neuronal hyperexcitability that contributes to neuropathic pain. These diseases focus attention on Nav1.7 and Nav1.8 as attractive therapeutic targets and stimulate the endeavour to develop subtype-specific drugs that selectively modulate these types of sodium channels.