Store-operated Ca(2+) entry (SOCE) is an important mechanism for Ca(2+) influx in non-excitable cells, also present in excitable cells. The activation of store-operated channels (SOCs) is finely regulated by the filling state of the intracellular agonist-sensitive Ca(2+) compartments, and both, the mechanism of sensing the Ca(2+) stores and the nature and functional properties of the SOCs, have been a matter of intense investigation and debate. The identification of STIM1 as the endoplasmic reticulum Ca(2+) sensor and both Orai1, as the pore-forming subunit of the channels mediating the Ca(2+)-selective store-operated current, and the members of the TRPC subfamily of proteins, as the channels mediating the cation-permeable SOCs, has shed new light on the underlying events. This review summarizes the initial hypothesis and the current advances on the mechanism of activation of SOCE.