Diagnosis and monitoring of multiple myeloma (MM) and related conditions are usually carried out by means of serum and urine protein electrophoresis and immunofixation. In the early 2000s, an assay aimed at evaluating serum free light chains (sFLCs) was made available and subsequently tested in different plasma cell disorders. Several reports have demonstrated the usefulness of the assay for the diagnosis and monitoring of oligosecretory MM, nonsecretory MM, Bence Jones MM, and amyloid light-chain amyloidosis. Furthermore, a prognostic role for an abnormal sFLC κ/λ ratio has been observed in the case of monoclonal gammopathy of unknown significance, smoldering MM, solitary plasmacytomas, and in newly diagnosed symptomatic MM secreting intact monoclonal immunoglobulins. In conclusion, according to present data, the sFLC assay can be considered reliable for the diagnosis, monitoring, and prognosis of different plasma cell disorders, and recently studies have been carried out to test a possible role of an sFLC evaluation in other B-cell lymphoproliferative malignancies.