In contrast with acquired pain syndromes, molecular substrates for hereditary pain disorders have been poorly understood. Familial erythromelalgia (Weir Mitchell's disease), also known as primary erythermalgia, is an autosomal dominant disorder characterized by burning pain in the extremities in response to warm stimuli or moderate exercise. The cause of this disorder has been enigmatic, and treatment has been empirical and not very effective. Recent studies, however, have shown that familial erythromelalgia is a channelopathy caused by mutations in the gene encoding the Na_v1.7 sodium channel which lead to altered channel function. Selective expression of Na_v1.7 within dorsal root ganglion neurons including nociceptors (in which this channel is targeted to sensory terminals, close to impulse trigger zones) and within sympathetic ganglion neurons explains why patients experience pain but do not suffer from seizures or other manifestations of altered excitability within central nervous system neurons. Erythromelalgia is the first human disorder in which it has been possible to associate an ion channel mutation with chronic neuropathic pain. Identification of mutations within a peripheral neuron‐specific sodium channel suggests the possibility of rational therapies that target the affected channel. Moreover, because some other pain syndromes, including acquired disorders, involve altered sodium channel function, erythromelalgia may emerge as a model disease that holds more general lessons about the molecular neurobiology of chronic pain. Ann Neurol 2005;57:785–788