Multiple myeloma is a disease characterized by a clonal expansion of plasma cells that secrete a monoclonal immunoglobulin also referred to as an M-protein. In the clinical laboratory, protein electrophoresis (PEL), immunofixation electrophoresis (IFE), and free light chain nephelometry (FLC) are used to detect, monitor, and quantify an M-protein. Here, we present an alternative method based on monitoring a clonotypic (i.e., clone-specific) peptide from the M-protein heavy chain variable region using LC-MS/MS. Tryptic digests were performed on IgG purified serum from 10 patients with a known IgG M-protein. Digests were analyzed by shotgun LC-MS/MS, and the results were searched against a protein database with the patient specific, heavy chain variable region gene sequence added to the database. In all 10 cases, the protein database search matched multiple clonotypic peptides from each patient's heavy chain variable region. The clonotypic peptides were then used to quantitate the amount of M-protein in patient serum samples using selected reaction monitoring (SRM) on a triple quadrupole mass spectrometer. The response for the clonotypic peptide observed by SRM correlated with the M-protein observed by PEL. In addition, the clonotypic peptide was clearly observed by SRM in samples that were negative by IFE and FLC. Monitoring clonotypic peptides using SRM has the capacity to redefine clinical residual disease because of its superior sensitivity and specificity compared with current analytical methods.