Ca(2+) release activated Ca(2+) (CRAC) channels mediate robust Ca(2+) influx when the endoplasmic reticulum Ca(2+) stores are depleted. This essential process for T-cell activation as well as degranulation of mast cells involves the Ca(2+) sensor STIM1, located in the endoplasmic reticulum and the Ca(2+) selective Orai1 channel in the plasma membrane. Our review describes the CRAC signaling pathway, the activation of which is initiated by a drop in the endoplasmic Ca(2+) level sensed by STIM1. This in term induces multimerisation and puncta-formation of STIM1 proteins is followed by their coupling to and activation of Orai channels. Consequently Ca(2+) entry is triggered through the Orai pore into the cytosol with subsequent closure of the channel by Ca(2+)-dependent inactivation. We will portray a mechanistic view of the events coupling STIM1 to Orai activation based on their structure and biophysics.