Integrins are important mediators of cell adhesion to extracellular ligands and can transduce biochemical signals both into and out of cells^1,2. The cytoplasmic domains of integrins interact with several structural and signalling proteins and consequently participate in the regulation of cell shape, motility, growth and differentiation³. It has been shown that calreticulin associates with the cytoplasmic domains of integrin α-subunits and that this interaction can influence integrin-mediated cell adhesion to extracellular matrix^4,5. We have now developed calreticulin-deficient embryonic stem (ES) cells and isolated embryonic fibro-blasts from calreticulin mutant mice. We find that in both cell types integrin-mediated adhesion is severely impaired, although integrin expression is unaltered. Expression of recombinant calreticulin in double knockout ES cells by complementary DNA transfection rescued integrin-mediated adhesion. In wild-type cells, engagement of surface integrins induced a transient elevation in cytosolic calcium concentration owing to influx of extracellular calcium. This calcium transient was absent in calreticulin-deficient cells. In contrast, the amount of calcium in endomembrane stores, which is sensitive to both inositol 1,4,5-trisphosphate and thapsigargin, was indistinguishable in the two cell types. Our results indicate that calreticulin is an essential modulator both of integrin adhesive functions and integrin-initiated signalling, but that it may not play a significant role in the storage of luminal calcium.