The most ubiquitous pathway for regulated calcium (Ca(2+)) entry into the cells is the store-operated Ca(2+) (SOC) entry pathway (also called capacitative Ca(2+) entry) that is conserved from lower organisms such as yeast, worms, and flies to man. The SOC concept was proposed over two decades ago, and SOC channels are defined by their activation in response to depletion of the internal Ca(2+) stores. Influx through SOC channels is necessary for the replenishment of the Ca(2+) stores and is also involved in cell signaling to the nucleus. Despite intensive investigations, most of which are focusing on transient receptor potential (TRP) channels as molecular candidates for SOC channels, the mechanisms of activation and the identity of the key molecular players participating in this signaling pathway have long remained elusive. In the last 2-3 years, however, the improvements of RNA silencing protocols combined with high throughput platforms have yielded significant breakthroughs, with the identification of Stim1 as the Ca(2+) store sensor and Orai1 (CRACM1) as the pore-forming subunit of the archetypical SOC channel, CRAC. This review summarizes the recent advances in the mechanisms of activation of SOC channels and their molecular composition, with emphasis on the roles of Stim, Orai, and TRP proteins.