During Ca2+ signalling, which regulates numerous essential eukaryotic cell functions, release of stored Ca2+ from the endoplasmic reticulum (ER) triggers the influx of Ca2+ across the plasma membrane through a process called store-operated Ca2+ entry (SOCE). The plasma membrane SOCE channels are comprised of subunits of the recently identified four-pass transmembrane Orai proteins. Now, on page 4354, James Putney and colleagues report that Orai1, the major Orai protein, exists as two isoforms in human cells. They show that the longer Orai1α and shorter Orai1β isoforms are the result of alternative translation initiation and are expressed in similar quantities in cell lines derived from several tissues. Orai1β lacks a poly-arginine sequence that is thought to be involved in the interaction of Orai1 with plasma membrane phosphatidylinositol 4,5-bisphosphate. Consistent with this loss, fluorescence recovery after photobleaching (FRAP) experiments indicate that Orai1β has a higher mobility in the plasma membrane than Orai1α. Because Orai1 has to diffuse to special ER-plasma membrane junctions called puncta to interact with the ER calcium sensor STIM1 (stromal interaction molecule 1), the authors suggest that the two Orai1 isoforms have specific functions in distinct modes of Ca2+ signalling.