Calreticulin (CRT) is a high-capacity, low-affinity Ca²⁺-binding protein located in the lumen of the endoplasmic reticulum (ER) of all eukaryotic cells investigated so far. Its high level of conservation among different species suggests that it serves functions fundamental to cell survival. The role originally proposed for CRT, i.e., the main Ca²⁺ buffer of the ER, has been obscured or even casted by its implication in processes as diverse as gene expression, protein folding, and cell adhesion. In this work we seek the role of CRT in Ca²⁺ storing and signaling by evaluating its effects on the kinetics and amplitude of the store-operated Ca²⁺ current (I _CRAC). We show that, in the rat basophilic leukemia cell line RBL-1, overexpression of CRT, but not of its mutant lacking the high-capacity Ca²⁺-binding domain, markedly retards the I _CRAC development, however, only when store depletion is slower than the rate of current activation. On the contrary, when store depletion is rapid and complete, overexpression of CRT has no effect. The present results are compatible with a major Ca²⁺-buffering role of CRT within the ER but exclude a direct, or indirect, role of this protein on the mechanism of I_CRAC activation.