The calcium-release-activated Ca 2+ channel, I CRAC, is a highly Ca 2+-selective ion channel that is activated on depletion of either intracellular Ca 2+ levels or intracellular Ca 2+ stores. The unique gating of I CRAC has made it a favourite target of investigation for new signal transduction mechanisms; however, without molecular identification of the channel protein, such studies have been inconclusive. Here we show that the protein CaT1 (ref. 4), which has six membrane-spanning domains, exhibits the unique biophysical properties of I CRAC when expressed in mammalian cells. Like I CRAC, expressed CaT1 protein is Ca 2+ selective, activated by a reduction in intracellular Ca 2+ concentration, and inactivated by higher intracellular concentrations of Ca 2+. The channel is indistinguishable from I CRAC in the following features: sequence of selectivity to divalent cations; an anomalous mole fraction effect; whole-cell current kinetics; block by lanthanum; loss of selectivity in the absence of divalent cations; and single-channel conductance to Na + in divalent-ion-free conditions. CaT1 is activated by both passive and active depletion of calcium stores. We propose that CaT1 comprises all or part of the I CRAC pore.