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Communication and material transfer between membranes and organelles take place at membrane contact sites (MCSs). MCSs between the ER and PM, the ER/PM junctions, are the sites where the ER Ca2+ sensor STIM1 and the PM Ca2+ influx channel Orai1 cluster. MCSs are formed by tether proteins that bridge the opposing membranes, but the identity and role of these tethers in receptor‐evoked Ca2+ signaling is not well understood. Here, we identified Anoctamin 8 (ANO8) as a key tether in the formation of the ER/PM junctions that is essential for STIM1‐STIM1 interaction and STIM1‐Orai1 interaction and channel activation at a ER/PM PI(4,5)P2‐rich compartment. Moreover, ANO8 assembles all core Ca2+ signaling proteins: Orai1, PMCA, STIM1, IP3 receptors, and SERCA2 at the ER/PM junctions to mediate a novel form of Orai1 channel inactivation by markedly facilitating SERCA2‐mediated Ca2+ influx into the ER. This controls the efficiency of receptor‐stimulated Ca2+ signaling, Ca2+ oscillations, and duration of Orai1 activity to prevent Ca2+ toxicity. These findings reveal the central role of MCSs in determining efficiency and fidelity of cell signaling. Synopsis: ER and plasma membrane (PM) form tight membrane intersections, where Ca2+ sensor STIM1 and influx channel Orai1 cluster to confer receptor‐stimulated signaling. A new screen identifies Anoctamin 8 (ANO8), a mammalian chloride channel family member, as key tether for ER/PM junctions, regulating STIM1‐Orai1 interactions and determining duration of Orai1‐dependent Ca2+ oscillations. ANO8 associates with STIM1 and Oria1 and controls their interaction.ANO8 increases STIM1‐Orai1 clusters at ER/PM junctions.ANO8 mediates slow, SARAF‐independent Orai1 inactivation at very low cytoplasmic calcium concentrations.ANO8 function depends on interaction with PM lipid PI(4,5)P2.ANO8 assembles all core calcium‐signaling factors at the PI(4,5)P2‐rich compartment. [ABSTRACT FROM AUTHOR]