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Voltage-gated sodium channels (Nav) that initiate electrical signals in excitable nerve and muscle cells are molecular targets for drugs and acquire disease mutations. These ion channels were first discovered in 1952 by researchers Hodgkin and Huxley who published landmark papers in The Journal of Physiology. The three key features of sodium channels discovered were voltage-dependent activation, rapid inactivation, and selective ion conductance. Since that time, a total of nine sodium channels have been discovered. The Nav isoforms of most interest as analgesic targets are Nav 1.3, Nav 1.7, Nav 1.8, and Nav 1.9 as they play specific roles in the neurobiology of pain and serve as potential analgesic targets. Knowledge of these channels’ structure and function, as well as their alterations in chronic pain, are vital to understanding how current sodium channel antagonists work but also for future drug developments. Currently, sodium channel antagonists fall into four pharmacological classes including anti-arrhythmics, anticonvulsants, local anesthetics, and antidepressants (discussed in another chapter). The sodium channel antagonists discussed in this chapter are considered nonselective.