Ca2+ is a signalling molecule involved in virtually every aspect of cell function. The endoplasmic reticulum (ER) is an important and dynamic organelle responsible for storage of the majority of intracellular Ca2+. Within the ER lumen are proteins that function as Ca2+ buffers and/or molecular chaperones including calreticulin, a multifunctional Ca2+-binding protein. Calreticulin-deficiency is lethal in utero due to impaired cardiac development. In the absence of calreticulin Ca2+ storage capacity in the ER and InsP(3) receptor mediated Ca2+ release from ER are compromised. Remarkably, over-expression of constitutively active calcineurin in the hearts of calreticulin deficient mice rescues them from embryonic lethality and produces live calreticulin deficient animals. These observations provide first evidence that calreticulin is a key upstream regulator of calcineurin in the Ca2+-signalling cascade and they highlight the importance of ER during early stages of cellular commitment and tissue development during organogenesis. (C) 2003 Elsevier Inc. All rights reserved.