Immunoelectrophoresis or immunofixation is necessary for the identification of a monoclonal protein. During 1990 at the Mayo Clinic, 787 patients were found to have a monoclonal gammopathy. IgG accounted for 61% of the cases, followed by IgM (18%), IgA (11%), Bence Jones proteinemia (6%), biclonal gammopathy (3.5%), and IgD (0.5%). Monoclonal gammopathy of undetermined significance accounted for approximately two thirds of patients. This denotes the presence of a monoclonal protein in persons without evidence of multiple myeloma, macroglobulinemia, amyloidosis, or other related diseases. During long-term follow-up of patients with monoclonal gammopathy of undetermined significance, we found that one fourth developed multiple myeloma or related disorders. The interval from recognition of the monoclonal gammopathy to the diagnosis of multiple myeloma ranged from 2 to 29 years (median, 10 years). Waldenström's macroglobulinemia developed in seven patients 4 to 20 years (median, 8.5 years) after recognition of the monoclonal protein. Systemic amyloidosis (AL) was found in eight patients 6 to 19 years (median, 9 years) after the diagnosis of a serum monoclonal protein. Five patients developed a malignant lymphoproliferative process 6 to 22 years (median, 10.5 years) after recognition of a monoclonal protein. Minimal criteria for the diagnosis of multiple myeloma include the presence of at least 10% abnormal plasma cells in the bone marrow or histologic proof of a plasmacytoma, the usual clinical features of multiple myeloma, and at least one of the following abnormalities: monoclonal serum protein (usually greater than 3 g/dL), monoclonal protein in the urine, or osteolytic lesions. No single technique differentiates benign from malignant plasma cell proliferation. The most dependable means is serial measurement of the monoclonal protein in the serum and urine and periodic reevaluation of pertinent clinical and laboratory features to determine whether multiple myeloma, systemic amyloidosis, macroglobulinemia, or other lymphoplasma cell proliferative disease has developed.