Calcium influx through plasma membrane store-operated Ca²⁺ (SOC) channels is triggered when the endoplasmic reticulum (ER) Ca²⁺ store is depleted — a homeostatic Ca²⁺ signalling mechanism that remained enigmatic for more than two decades. RNA-interference (RNAi) screening and molecular and cellular physiological analysis recently identified STIM1 as the mechanistic 'missing link' between the ER and the plasma membrane. STIM proteins sense the depletion of Ca²⁺ from the ER, oligomerize, translocate to junctions adjacent to the plasma membrane, organize Orai or TRPC (transient receptor potential cation) channels into clusters and open these channels to bring about SOC entry.