Calreticulin is a Ca(2+)-binding chaperone of the sarcoplasmic/endoplasmic reticulum. It is an important Ca(2+) buffer, a regulator of Ca(2+) homeostasis, and a component of protein quality control processes in the secretory pathway. Calreticulin is essential for cardiac development; its gene is tightly regulated during cardiogenesis, and in the absence of calreticulin, cardiac development is impaired. The protein is highly expressed in the developing heart and down-regulated after birth in the healthy mature heart. Overexpression of calreticulin in postnatal heart leads to bradyarrhythima and complete heart block, followed by sudden death. The calreticulin gene is a target of transcription factors involved in fetal cardiac program (Nkx2.5, myocardin, myocyte enhancer factor 2C, and GATA6). Calreticulin works upstream of calcineurin and myocyte enhancer factor 2C in a Ca(2+)-dependent signal transduction cascade linking the endoplasmic reticulum and the nucleus during cardiac development.