Store-operated calcium entry (SOCE) is an important calcium entry pathway in non-excitable cells. Stromal interaction molecule 1 (STIM1) – a transmembrane phosphoprotein located in the endoplasmic reticulum (ER) – is a key regulator of SOCE. When the calcium concentration in the ER falls, STIM1 aggregates and relocates close to the plasma membrane, where it activates store-operated calcium channels – but does STIM1 phosphorylation affect this function? On page 3084, Francisco Javier Martín-Romero and colleagues reveal for the first time that phosphorylation of STIM1 at extracellular-signal-regulated kinases 1 and 2 (ERK1/2) sites modulates SOCE. They identify Ser575, Ser608 and Ser621 as ERK1/2 phosphorylated sites in STIM1, and show that alanine substitution at these target sites or treatment with ERK1/2 inhibitors reduces SOCE in HEK293 cells. 12-O-tetradecanoylphorbol-13-acetate activation of ERK1/2, they report, enhances SOCE in cells expressing wild-type STIM1, but not in cells expressing STIM1 with alanine mutations at the ERK1/2 target sites. Finally, alanine mutation of its ERK1/2 target residues reduces STIM1 binding to store-operated calcium channels. Together, these results reveal a mechanism whereby STIM1 phosphorylation modulates SOCE.