Lanthanides (Lns) have been shown recently to be essential cofactors in certain enzymes in methylotrophic bacteria. Here we identify in the model methylotroph, Methylobacterium extorquens, a highly selective Ln(III)-binding protein, which we name lanmodulin (LanM). LanM possesses four metal-binding EF hand motifs, commonly associated with Ca-II-binding proteins. In contrast to other EF hand-containing proteins, however, LanM undergoes a large conformational change from a largely disordered state to a compact, ordered state in response to picomolar concentrations of all Ln(III) (Ln = La-Lu, Y), whereas it only responds to Ca-II at near-millimolar concentrations. Mutagenesis of conserved proline residues present in LanM's EF hands, not encountered in Ca-II-binding EF hands, to alanine pushes Ca-II responsiveness into the micromolar concentration range while retaining picomolar Ln(III) affinity, suggesting that these unique proline residues play a key role in ensuring metal selectivity in vivo. Identification and characterization of LanM provides insights into how biology selectively recognizes low-abundance Ln(III) over higher-abundance Ca-II, pointing toward biotechnologies for detecting, sequestering, and separating these technologically important elements.