THE protein IsK (M14,500) is present in epithelial cells1, heart2,3, uterus4 and lymphocytes5 and induces slowly activating K+ currents when expressed in Xenopus oocytes1. The finding that mutations of its single transmembrane segment altered channel gating6 or selectivity7 has suggested that IsK is a channel-forming protein. But IsK does nof exhibit the K+ channel hallmarks8 (a conserved K+ selective pore (H5) flanked by either six9-11 or two12,13 membrane-spanning regions). Here we report that IsK expression in Xenopus oocytes also induces a Cl- selective current very similar to the Cl- current produced by phospholemman expression14 and with biophysical, pharmacological and regulation characteristics very different from those of the IsK-induced K+ channel activity. IsK mutagenesis identifies amino- and carboxy-terminal domains as critical for the induction of Cl- and K+ channel activities, respectively. Our data lead to a model in which the IsK protein (now called IsK, Cl) acts as a potent activator of endogenous and otherwise silent K+ or Cl- channels.