Monoclonal gammopathy of renal significance (MGRS) is a group of diseases with different renal damage. It is a new type of renal disease with various types of diseases and complex disease mechanism. In MGRS, due to the clonal proliferation of B lymphoid cells or plasma cells, a large number of monoclonal immunoglobulin (MIg) and/or a large number of free light chain (FLC) appear. Intact MIg can interact with intrinsic cells of glomerulus to change its biology in order to promote the development of renal disease, while monoclonal FLC can potentially alter the function of various cells throughout the nephron. Given the relationship of MIg and monoclonal FLC to MGRS, inhibition of MIg and monoclonal FLC would be a promising approach for the treatment of MGRS. This paper reviews the pathogenesis of MGRS from the sites of renal involvement, including glomerulus, renal tubule-interstitium and renal blood vessel.