Voltage-gated sodium channels are among the most active and ubiquitous molecular machines found in animals. Residing in the cell membranes of excitable and other cells, they derive energy for their opening and closing from changes in membrane potential. In some cells, particularly those in sensory information–encoding structures of the central and peripheral nervous systems, these changes take place repetitively every few milliseconds, making the channel gates some of the most conformationally versatile structures of nature. The ion channel–lining domain, also called the α subunit, is particularly prone to mutations that alter channel production and targeting, ion conduction, or gate action. Particularly interesting are mutations that render ion channel gates more or less prone to opening. These mutations are a significant cause of abnormal pain sensation in man, a largely unmet medical need and a fascinating biophysical phenomenon. Channels are inherently capable of opening and closing, allowing or blocking sodium ions from traveling through the pore. In fact, they can do so spontaneously, traversing a variety of different conformational states over time. Some states are energetically more favored than others; however, such that little or no significant opening is detectable at rest (when cells are hyperpolarized). What membrane potential does, in the case of sodium channels, is favor some of these states, resulting in the net dwelling of the ion channel in open or closed conformation.