Calcium (Ca(2+)) entry into non-excitable cells is mainly carried by store-operated channels (SOCs), which serve essential functions ranging from regulation of transcription to cell growth. The best-characterized store-operated current, I(CRAC), is the calcium release-activated calcium (CRAC) current initially discovered in T-lymphocytes and mast cells. The search for the molecular components of the CRAC channel lasted over 20 years. Recently STIM1 has been identified as the Ca(2+) sensor in the endoplasmic reticulum (ER) that accumulates into punctae close to the plasma-membrane following store-depletion. The identification of STIM1 has been closely followed by the discovery of Orai1 as the CRAC channel pore in human T-cells. Upon punctae formation STIM1 activates Ca(2+) influx via Orai1 channels. This review covers functional details concerning the activation cascade of the STIM1/Orai1 complex from ER Ca(2+) sensing to Ca(2+) influx through Orai1. Furthermore, functional domains within STIM1 and Orai1 in comparison to their structural homologs STIM2 as well as Orai2 and Orai3, respectively, are displayed together with recent findings on the pore architecture and selectivity filter of Orai channels. A broad tissue expression of STIM and Orai proteins together with substantial effects in STIM1/Orai1 knock-out mice suggests an essential physiological role in store-operated Ca(2+) signalling in human health and disease.