If swelling of a cell is induced by a decrease in external medium tonicity, the regulatory response is more complex than if swelling of similar magnitude is due to salt uptake. The present results provide an explanation. In fish erythrocytes, two distinct transport pathways were swelling activated: a channel of broad specificity and a K+-Cl−cotransporter. Each was activated by a specific signal: the channel by a decrease in intracellular ionic strength and the K+-Cl−cotransporter by cell enlargement. A decrease in ionic strength also affected K+-Cl−cotransport activity, but by acting as a negative modulator of the cotransport. Thus cells swollen by salt accumulation respond by activating exclusively the K+-Cl−cotransport, leading to a Cl−-dependent K+ loss. By contrast, cells swollen by electrolyte dilution respond by activating both pathways, leading to a reduced loss of electrolytes and a large loss of taurine. Thus two swelling-sensitive pathways, differently regulated, would allow control of the ionic composition of a cell exposed to different volume perturbations.