Membrane currents of Xenopus oocytes were studied with the membrane under voltage clamp. Intracellular injection of the calcium-chelating agent EGTA reduced, or abolished, the transient outward chloride current normally activated by membrane depolarization. Intracellular injection of calcium ions evoked large membrane currents, which inverted direction close to the chloride equilibrium potential. Injections of strontium, or barium, were less effective than calcium, while magnesium was ineffective. Large chloride currents could be evoked by calcium injections in oocytes which showed only small or no transient outward currents. The current activated by calcium injection increased with increasing depolarization up to high (ca. +60 mV) positive potentials, even though the transient outward current was suppressed by strong depolarization. The results indicate that the transient outward current depends upon entry of calcium through voltage-gated calcium ion channels and show that the oocyte membrane contains numerous chloride channels which are activated by intracellular calcium. Only a few of these chloride channels are activated by depolarization.