The Orai channels are unusual, yet prominent, calcium (Ca(2+)) signal mediators in most cell types. Orai proteins are structurally unique, having little sequence homology with other ion channels. They are also functionally unique with exceedingly high selectivity for Ca(2+), mediating both short-term Ca(2+) homeostasis and long-term Ca(2+) signals important for transcriptional control. Operating in the plasma membrane (PM), Orai channel regulation is unprecedented among ion channels; channel gating occurs through an elaborate intermembrane coupling with stromal interaction molecule (STIM) proteins in the endoplasmic reticulum (ER). STIM proteins function as sensors of Ca(2+) stored in the ER lumen and translocate into ER-PM junctions to tether and activate Orai channels when ER Ca(2+) concentration decreases. Crystallization studies reveal an unexpected hexameric structure for the Orai channel and provide important insights into the pore architecture, the structural basis of its unusual cation selectivity, and how channel gating occurs through its coupling with STIM proteins.