The term monoclonal gammopathy of renal significance (MGRS) was introduced to describe renal damage caused by monoclonal immunoglobulin (MIg) secreted by small B-cell clones. By definition, patients with MGRS do not meet the diagnostic criteria of hematological malignancies such as multiple myeloma and lymphoma. MIg produced by these clones can result in permanent renal damage through its direct or indirect mechanisms. The spectrum of renal diseases in MGRS is wide, and early diagnosis is helpful for guiding the treatment and improving the prognosis. The diagnosis requires the combination of renal morphologic alterations from light microscopy, immunofluorescence (IF), and electron microscopy, with complete hematologic workup such as serum and urine protein electrophoresis, immunofixation, and serum light-chain assay. The treatment of MGRS includes conventional therapy, chemotherapy based on protease inhibitors, cytotoxic drugs, immunomodulators, and stem cell transplantation. The therapeutic strategy of MGRS targeting the causal B-cell clones is similar to the equivalent extrapolation treatments used for the overt malignancies. In addition, timely evaluation of the hematologic responses can be conducive to determining the efficacy of treatment, and prolonging the overall survival time.