Ca2+ release-activated Ca2+ channels mediate a sustained Ca2+ influx following depletion of endoplasmic reticulum stores. This signalling cascade that triggers T-cell activation or mast cell degranulation involves STIM1, the Ca2+ sensor in the endoplasmic reticulum, and the Ca2+ selective Orai channel in the plasma membrane. This review describes the molecular mechanism (s) governing the STIM1/Orai signalling machinery. Moreover, we provide an overview on additional proteins modulating or interacting with the STIM1/Orai1 system. A structure-function relationship highlights regions within STIM1/Orai proteins contributing to activation, permeation and inactivation of CRAC currents.