The voltage-gated sodium, calcium, and potassium channels are responsible for the generation of conducted electrical signals in neurons and other excitable cells. The pemleability increase resulting from activation of these channels is biphasic. Upon depolarization, permeability to sodium, calcium, or potassium increases dramatically over a period of 0.5 to hundreds of msec and then decreases to the baseline level over a period of 2 msec to a few seconds. This biphasic behavior results from two experimentally separable gating processes that control ion channel function: activation, which controls the rate and voltage dependence of the permeability increase following depolarization, and inactivation, which controls the rate and voltage dependence of the subsequent return of the ion permeability to the resting level during a maintained depo larization. The voltage-gated ion channels can therefore exist in three func tionally distinct states or groups of states: resting, active, and inactivated. Both resting and inactivated states are nonconducting, but channels that have been inactivated by prolonged depolarization are refractory unless the cell is repo larized to allow them to return to the resting state. The ion conductance of the activated ion channels is both highly selective and remarkably efficient. Se lectivity among the physiological ions ranges from 12-fold for sodium channels to over lOOO-fold for calcium channels, and all three classes of ion channels conduct ions across biological membranes at rates approaching their rates of free diffusion through solution. Understanding the molecular bases for volt age-dependent activation, rapid inactivation, and selective and efficient ion conductance is a major goal of current research on these critical signaling proteins.