Exposure of isolated frog skeletal muscle to a cardiac glycoside produces changes in the prejunctional events associated with neuromuscular transmission. The principal changes consist of a progressive increase in the quantum content of the end-plate potential, followed by conduction block in intramuscular motor nerve branches. These events are accompanied by a progressive increase in the frequency of miniature end-plate potentials. Following conduction blockade spontaneous end-plate potentials occur which arise from the generation of action potentials at or near the nerve terminations. Still later, the miniature end-plate potential frequency declines and the nerve endings become entirely inexcitable. These changes appear to result from inhibition of a sodium pump in the motor nerve axons and their endings.