Hodgkin and Huxley’s seminal studies on the squid giant axon – carried out before the advent of patch clamp or modern molecular biology – clearly established the pivotal role of sodium channels in action potential conduction. Since then, it has become clear that there are ten isoforms of sodium channels, sharing a common overall motif but with different amino acid sequences and different physiological properties. This review will examine recent progress on the roles of these different sodium channels in mammalian neurons, with emphasis on their multiple roles in the human nervous system, both healthy and diseased, using multiple sclerosis and neuropathic pain as model diseases. We will discuss the role of specific sodium channels in driving reverse sodium-calcium exchange which triggers axonal degeneration and irreversible worsening, and the role of other sodium channels in restoring conduction along demyelinated axons, which permits remission (recovery of function) in multiple sclerosis. We will also discuss changes in sodium channel expression following axonal injury which contribute to DRG neuron hyperexcitability that underlies neuropathic pain. Finally, we will describe loss-of-function and gain-of-function mutations of the Nav1.7 sodium channel which produce insensitivity to pain, and the “man on fire” syndrome, erythromelalgia, in humans, and which both establish the role of this channel in human nociception and suggest new therapeutic strategies. These examples underscore the continuing relevance of the original studies on sodium channels, carried out in a model system, the squid.