Identification of monoclonal gammopathies in serum has involved electrophoresis of serum proteins, immunoelectrophoresis (IEP), and quantification of IgG, IgA, and IgM. Recent innovations in technology--including high-resolution electrophoresis (HRE), immunofixation (IFX), and quantification of kappa- and lambda-containing immunoglobulins--allow for more rapid and precise assessment of serum for monoclonal proteins. We present a series of guidelines to determine when high-resolution electrophoresis and quantification of immunoglobulins (including kappa and lambda) are sufficient and when additional IFX is required to characterize the monoclonal gammopathy. Of the samples studied, 88% were correctly diagnosed by HRE with quantification of immunoglobulins and kappa/lambda; only 12% required that IFX be performed. The guidelines allow us to detect monoclonal gammopathies quicker and more efficiently by avoiding redundant IEP or IFX testing. For the vast majority of cases, these guidelines allow for a correct diagnosis within one day. After one year of follow-up since completion of the study, no undetected cases of monoclonal gammopathy have eventuated.