Besides initiating and propagating action potentials in established neuronal circuits, voltage-dependent sodium channels sculpt and bolster the functional neuronal network from early in embryonic development through adulthood (e.g., differentiation of oligodendrocyte precursor cells into oligodendrocytes, myelinating axon; competition between neighboring equipotential neurites for development into a single axon; enhancing and opposing functional interactions with attractive and repulsive molecules for axon pathfinding; extending and retracting terminal arborization of axon for correct synapse formation; experience-driven cognition; neuronal survival; and remyelination of demyelinated axons). Surprisingly, different patterns of action potentials direct homeostasis-based epigenetic selection for neurotransmitter phenotype, thus excitability by sodium channels specifying expression of inhibitory neurotransmitters. Mechanisms for these pleiotropic effects of sodium channels include reciprocal interactions between neurons and glia via neurotransmitters, growth factors, and cytokines at synapses and axons. Sodium channelopathies causing pain (e.g., allodynia) and neurodegeneration (e.g., multiple sclerosis) derive from 1) electrophysiological disturbances by insults (e.g., ischemia/hypoxia, toxins, and antibodies); 2) loss-of-physiological function or gain-of-pathological function of mutant sodium channel proteins; 3) spatiotemporal inappropriate expression of normal sodium channel proteins; or 4) de-repressed expression of otherwise silent sodium channel genes. Na_v1.7 proved to account for pain in human erythermalgia and inflammation, being the convincing molecular target of pain treatment.