Voltage clamp measurements on squid giant axons show that externally applied puffer fish poison, tetrodotoxin, eliminates only the initial inward current component of spike electrogenesis and does not affect the subsequent outward current. The selective effect on Na activation, which is reversible, confirms the view that the movements of Na and K during spike electrogenesis occur at structurally different sites on the membrane. Spike electrogenesis is also blocked when tetrodotoxin is injected into the axon, but the interior of the membrane appears to be somewhat less sensitive to the poison. Differences in reactivity of various electrogenic membrane components to tetrodotoxin are discussed as signifying differences in chemical structures.