Stromal interaction molecules (STIM1 and STIM2) are critical components of store-operated calcium entry. Sensing depletion of endoplasmic reticulum (ER) Ca²⁺ stores, STIM couples with plasma membrane Orai channels, resulting in the influx of Ca²⁺ across the PM into the cytosol. Although best recognized for their primary role as ER Ca²⁺ sensors, increasing evidence suggests that STIM proteins have a broader variety of sensory capabilities than first envisaged, reacting to cell stressors such as oxidative stress, temperature, and hypoxia. Further, the array of partners for STIM proteins is now understood to range far beyond the Orai channel family. Here we discuss the implications of STIM’s expanding role, both as a stress sensor and a general modulator of multiple physiological processes in the cell.