Abstract Voltage-gated Na+ channels exhibit three states: closed activatable, open activated, and closed inactivatable. At resting membrane potentials, about 75% of the channels are in the closed activatable state. Depolarizing the axon membrane causes the activatable channels to open, allowing Na+ to move along a voltage and concentration gradient, which further depolarizes the membrane and results in a propagated action potential. At the nerve terminal, neurotransmitters are released by the invading action potential to act on cell receptors adjacent to the terminal or systemically if the transmitter is released into the blood. Regulated current pulses are the preferred method of electrically activating a nerve because the induced field remains constant during the stimulus pulse. When voltage pulses are used, the injected current is a function of electrode–tissue impendence and the current decays with time, meaning that the excitatory field decays with time. Cathodic currents are more effective in initiating propagating action potentials on axons because depolarizing currents are more concentrated near the electrode. Depolarizing currents are more widely distributed when anodic stimulation is applied, which means that larger currents must be used to reach threshold depolarization with anodic stimuli. Short-duration high-amplitude stimuli require less charge to initiate a propagated action potential than do low-amplitude long-duration stimuli. In general, less charge injection generates fewer electrochemical reaction products and draws less power. The effect of an applied stimulus is always greater on larger-diameter axons than on smaller-diameter axons, because internodal spacing is greater in larger axons than it is in smaller ones. The effect of the applied stimulus is always greater on axons that are closer to the electrode than on axons farther from the electrode. This means that when a cathodic stimulus is applied to an axon, the threshold for activation of larger fibers will lower than that required to activate smaller fibers, if they are at the same distance from the electrode. Driving the electrode interface potential anodically can result in loss of electrode metal and the creation of metallic salts that are powerful oxidizing agents. To avoid oxidizing the electrode, the amount of charge injected in the anodic phase may be limited by using imbalanced biphasic pulses or lower charge injection with balanced biphasic stimuli.