Store-operated calcium channels (SOCs) are a nearly ubiquitous Ca(2+) entry pathway stimulated by numerous cell surface receptors via the reduction of Ca(2+) concentration in the ER. The discovery of STIM proteins as ER Ca(2+) sensors and Orai proteins as structural components of the Ca(2+) release-activated Ca(2+) (CRAC) channel, a prototypic SOC, opened the floodgates for exploring the molecular mechanism of this pathway and its functions. This review focuses on recent advances made possible by the use of STIM and Orai as molecular tools. I will describe our current understanding of the store-operated Ca(2+) entry mechanism and its emerging roles in physiology and disease, areas of uncertainty in which further progress is needed, and recent findings that are opening new directions for research in this rapidly growing field.