The ability to precisely regulate cell volume is a fundamental property of most cells. Although the phenomenon of regulatory volume decrease (RVD), whereby a swollen cell loses salt and water to restore its original volume, has been appreciated for decades, the molecular identities of the proteins responsible for the volume control machinery and their regulation are essentially unknown. It appears that the rate-determining step in gaining volume control involves the activation of potassium and chloride conductance pathways. We have identified a native chloride current (ICl.swell) responsive to cell swelling in Xenopus oocytes [Ackerman et al. (1994) J Gen Physiol 103: 153-179]. Moreover, we have demonstrated that a cloned protein, pICln, endogenous to oocytes is critical for the activation of this volume-sensitive chloride conductance pathway [Krapivinsky et al. (1994) Cell 76: 439-448]. The identification of an endogenous protein participating in the regulation of an endogenous current may help understand the physiological activities of swelling-induced chloride channels.