Cell swelling is counteracted by activation of potassium and chloride conductances. The loss of these ions imposes a passive efflux of water that consequently decreases the cell volume. This homeostatic response is called regulatory volume decrease. A key element of this response is the activation of chloride channels as consequence of cell swelling. The molecular nature of these channels is very much debated and remains still an unsettle issue. The biophysical characteristics of the swelling-activated current as well as its modulation will be analyzed. The proposed candidates for the swelling-activated chloride channels will be reviewed.