Calmodulin (CaM) binds in a Ca2+-dependent manner to the intracellular C-terminal domains of most group III metabotropic glutamate receptors (mGluRs). Here, we combined mutational and biophysical approaches to define the structural basis of CaM binding to mGluR 7A. Ca2+/CaM was found to interact with mGluR 7A primarily via its C-lobe at a 1:1 CaM:C-tail stoichiometry. Pull-down experiments with mutant CaM and mGluR 7A C-tail constructs and high-resolution NMR with peptides corresponding to the CaM binding region of mGluR 7A allowed to define hydrophobic and ionic interactions required for Ca2+/CaM binding and identified a 1-8-14 CaM binding motif. The Ca2+/CaM-mGluR 7A peptide complex displays a classical wrap-around structure that closely resembles that formed by Ca2+/CaM upon binding to smooth muscle myosin light chain kinase. Our data provide insight into how Ca2+/CaM regulates group III mGluR signaling via competition with intracellular proteins for receptor binding sites.