In essentially all eukaryotic cells, activation of phospholipase C (PLC)-coupled receptors leads to inostitol1,4,5-trisphosphate (IP3)-dependent depletion of endoplasmic reticulum (ER) Ca2+ stores. ER Store depletion is sensed by Stromal-interaction molecule 1 (STIM1), which then activate Orai1 channels located in the plasma membrane (PM). STIM1/Orai1 coalesce within ER-PM junctions and generate Ca2+ nanodomains crucial for activation gene programs, including those driven by Calcineurin/nuclear factor for activated T-cells (NFAT) that regulate cell motility, growth, and metabolism. ER-mitochondria contact sites and functional PM-mitochondria interactions further shape receptor-evoked Ca2+ signaling to fine-tune cell function. In turn, mitochondrial Ca2+ uptake and extrusion, through the mitochondrial Ca2+ uniporter (MCU) and the Na+/Ca2+/Li+ exchanger (NCLX) respectively, are crucial for proper mitochondrial function and for coupling receptor stimulation to cellular bioenergetics. While the essential role of STIM1 and Orai1 in receptor evoked Ca2+ signaling is well understood, little is known about the physiological activation and the choreography of interactions between the five STIM1,2/Orai1,2,3 proteins natively expressed in all mammalian cells. Here we will discuss our recent findings revealing that coordinated functions of the five STIM1,2/Orai1,2,3, IP3 receptors, MCU and NCLX at the ER-PM and ER-mitochondria contact sites translate the strength of agonist stimulation to precise levels of Ca2+ signaling and NFAT induction, ensuring the fidelity of complex mammalian Ca2+ signaling.