Store-operated calcium entry is a central mechanism in cellular calcium signalling and in maintaining cellular calcium balance. This review traces the history of research on store-operated calcium entry, the discovery of STIM and ORAI as central players in calcium entry, and the role of STIM and ORAI in biology and human disease. It describes current knowledge of the basic mechanism of STIM-ORAI signalling and of the varied mechanisms by which STIM-ORAI signalling can be modulated. (C) 2015 Elsevier Inc. All rights reserved.