Deviations in basal Ca²⁺ levels interfere with receptor-mediated Ca²⁺ signaling as well as endoplasmic reticulum (ER) and mitochondrial function. While defective basal Ca²⁺ regulation has been linked to various diseases, the regulatory mechanism that controls basal Ca²⁺ is poorly understood. Here we performed an siRNA screen of the human signaling proteome to identify regulators of basal Ca²⁺ concentration and found STIM2 as the strongest positive regulator. In contrast to STIM1, a recently discovered signal transducer that triggers Ca²⁺ influx in response to receptor-mediated depletion of ER Ca²⁺ stores, STIM2 activated Ca²⁺ influx upon smaller decreases in ER Ca²⁺. STIM2, like STIM1, caused Ca²⁺ influx via activation of the plasma membrane Ca²⁺ channel Orai1. Our study places STIM2 at the center of a feedback module that keeps basal cytosolic and ER Ca²⁺ concentrations within tight limits.