Although many aspects of the physiological and pathophysiological mechanisms remain unknown, recent advances in our knowledge suggest that the CREC proteins are promising disease biomarkers or targets for therapeutic intervention in a variety of diseases. The CREC family of low affinity, Ca2+‐binding, multiple EF‐hand proteins are encoded by five genes,RCN1,RCN2,RCN3,SDF4, andCALU, resulting in reticulocalbin, ER Ca2+‐binding protein of 55 kDa (ERC‐55), reticulocalbin‐3, Ca2+‐binding protein of 45 kDa (Cab45), and calumenin. Alternative splicing increases the number of gene products. The (...) proteins are localized in the cytosol, in various parts of the secretory pathway, secreted to the extracellular space or localized on the cell surface. The emerging functions appear to be highly diverse. The proteins interact with several different ligands. Rather well‐described functions are attached to calumenin with the inhibition of several proteins in the endoplasmic or sarcoplasmic reticulum membrane, the vitamin K12,3‐epoxide reductase, the γ‐carboxylase, the ryanodine receptor, and the Ca2+‐transporting ATPase. Other functions concern participation in the secretory process, chaperone activity, signal transduction as well as participation in a large variety of disease processes. (shrink)