We have examined some of the physiological effects associated with the replacement of extracellular Na+ with Li+ in nominally Ca(2+)-free saline in the ventral photoreceptors of the horseshoe crab Limulus polyphemus. We observed that replacement of Na+ saline with Li+ saline induced larger voltage-activated inward currents with similar voltage dependence. These currents were absent in Tris+ saline. Anode-break excitation was maintained in Li+ saline but blocked in Tris+ saline. Regenerative events associated with quantum bumps in dark-adapted cells illuminated with dim lights were maintained in Li+ saline. Regenerative events associated with responses to moderately bright illumination were also maintained in Li+ saline. The post-illumination hyperpolarization associated with the Na+/K(+)-exchange pump (Brown & Lisman, 1972) was present after brief exposure to Li+ saline but disappeared after longer exposure. Following return to Na+ saline, the post-illumination hyperpolarization reappeared. We conclude that (1) Li+ permeates the voltage-dependent Na+ channel, GNa(V), in the photoreceptor plasma membrane; (2) Li+ supports voltage-activated physiological events normally mediated by Na+; and (3) Li+ substitution briefly supports and later inhibits the electrogenic effects of the Na+/K(+)-exchange pump. The effects of external Li+ on cellular physiology have implications for the interpretation of other studies employing Li+ extracellularly.