The Ca(2+)-sensing receptor (CaSR) is a member of family C of the GPCRs responsible for sensing extracellular Ca(2+) ([Ca(2+)](o)) levels, maintaining extracellular Ca(2+) homeostasis, and transducing Ca(2+) signaling from the extracellular milieu to the intracellular environment. In the present study, we have demonstrated a Ca(2+)-dependent, stoichiometric interaction between CaM and a CaM-binding domain (CaMBD) located within the C terminus of CaSR (residues 871-898). Our studies suggest a wrapping around 1-14-like mode of interaction that involves global conformational changes in both lobes of CaM with concomitant formation of a helical structure in the CaMBD. More importantly, the Ca(2+)-dependent association between CaM and the C terminus of CaSR is critical for maintaining proper responsiveness of intracellular Ca(2+) responses to changes in extracellular Ca(2+) and regulating cell surface expression of the receptor.