Multiple myeloma and MGUS are the two most common causes of monoclonal protein in serum or urine. The usually accepted diagnostic triad for multiple myeloma consists of a significant paraprotein in the serum or urine, more than 10% to 15% plasma cells in bone marrow, and the presence of bony lesions. Patients who meet the first two criteria but have no bony lesions, cytopenias, renal failure, or hypercalcemia may have smoldering myeloma, which often can be observed for a period of time before therapy is required. MGUS is characterized by a serum IgG monoclonal protein less than 3.5 g/dL or IgA paraprotein less than 2 g/dL, with no or only a small amount of protein in urine (Bence Jones protein < 1 g/24 hr). Less than 10% plasma cells are present in bone marrow, and patients have no lytic bony lesions, anemia, hypercalcemia, or renal insufficiency. Another important criterion for MGUS is stability of the monoclonal protein over time. Nonetheless, during long-term follow-up, an associated malignant process develops in about 30% of MGUS patients. Since none of the features defining MGUS is uniformly helpful in predicting the risk for malignant disease, patients should be followed up on a regular basis indefinitely.