Summary STIM1 in the endoplasmic reticulum and CRACM1 in the plasma membrane are essential molecular components for controlling the store-operated CRAC current [1–4]. CRACM1 proteins multimerize and bind STIM1 [5, 6], and the combined overexpression of STIM1 and CRACM1 reconstitutes amplified CRAC currents [7–10]. Mutations in CRACM1 determine the selectivity of CRAC currents, demonstrating that CRACM1 forms the CRAC channel's ion-selective pore [11, 5, 6], but the CRACM1 homologs CRACM2 and CRACM3 are less well characterized [7, 12]. Here, we show that both CRACM2 and CRACM3, when overexpressed in HEK293 cells stably expressing STIM1, potentiate I CRAC to current amplitudes 15–20 times larger than native I CRAC. A nonconducting mutation of CRACM1 (E106Q) acts as a dominant negative for all three CRACM homologs, suggesting that they can form heteromultimeric channel complexes. All three CRACM homologs exhibit distinct properties in terms of selectivity for Ca 2+ and Na +, differential pharmacological effects in response to 2-APB, and strikingly different feedback regulation by intracellular Ca 2+. Each of the CRAC channel proteins' specific functional features and the potential heteromerization provide for flexibility in shaping Ca 2+ signals, and their characteristic biophysical and pharmacological properties will aid in identifying CRAC-channel species in native cells that express them.