Membranous nephropathy is one of the most common diseases affecting the glomerulus, an important part of the kidney responsible for filtration of blood. Glomeruli are networks of capillaries that filter blood; normally only small ions and proteins are filtered, while larger proteins like hemoglobin, albumin, and immunoglobulins are retained. The filtration barrier consists of several layers including: capillary endothelial cells, glomerular basement membrane, and specialized cells called podocytes. In patients with membranous nephropathy, this selective barrier is injured, leading to massive loss of proteins in urine (proteinuria). Patients typically present with marked swelling due to protein loss and avid sodium absorption by the kidneys, as well as hypoalbuminemia, hyperlipidemia, lipiduria, and propensity for developing infections and clots (called nephrotic syndrome). Histopathologically, this disorder is characterized by discovery of immune deposits in a specific part of glomerulus between the basement membrane and podocyte (called subepithelium). Membranous nephropathy can be primary (idiopathic) or secondary when caused by malignancy, infections, autoimmune diseases or drugs. Idiopathic membranous nephropathy (IMN) is classically believed to be progressive in one third of cases, while the other two thirds remain stable or improve spontaneously [1]. Tremendous insights into the pathophysiology of IMN have been made recently, with studies that have identified key antigens and cemented our understanding of the mechanisms of this disease. The first insights which paved the way to our current understanding of IMN came from a rat model called Heymann’s nephritis [2, 3]. The rats had subepithelial deposits consisting of megalin and megalin-specific circulating antibodies [3]. What puzzled scientists and clinicians was that megalin was not expressed in human podocytes, and could thus not be the target antigen in human IMN [4]. Another rare cause of IMN demonstrated the same principle of injury, and this was the occurrence of IMN in neonates with circulating anti-neutral endopeptidase antibodies [5, 6]. Mothers of these neonates had genetic deficiency in neutral endopeptidase, and through immunization produced antibodies to neutral endopeptidase present in podocytes of the fetus. Disappearance of these antibodies led to cure. The most significant discovery along the same paradigm was that of M-type phospholipase A2 receptor (PLA2R) antibodies as the causative agent in most patients with IMN [7]. PLA2R is expressed in the podocyte and remains the most convincing antigen in IMN. Anti-PLA2R antibody in serum identifies approximately 70 – 80% of cases of IMN in Caucasians [7, 8], African Americans [7] and Chinese patients [9]. Immunostaining of biopsies from patients with IMN detects increased deposition of subepithelial PLA2R with similar sensitivity to serum anti-PLA2R levels [10]. A genome wide association study identified a significant association between PLA2R-related SNPs and IMN [11]. Finally, level of the anti-PLA2R antibody in serum appears to parallel response to Rituximab [12], a chimeric monoclonal antibody against the B cell surface antigen CD20. The level of anti-PLA2R antibody may also correlate with IMN relapse after kidney transplantation [13]. This represents an important pharmacoproteomic finding relating to response to an immunomodulatory agent in IMN. There is also preliminary evidence that this antibody mirrors disease activity [8]. Despite the undeniable potential of anti-PLA2R antibodies as a biomarker of disease in patients with IMN, this antibody does not explain the etiology of the disease in a substantial proportion of cases. It is tempting to speculate that antibodies to distinct podocyte antigens are responsible for these “PLA2R negative” cases. Indeed, aldose reductase (AR) and superoxide dismutase 2 (SOD2) [14] were discovered as additional podocyte antigens linked with IMN, and are likely responsible for a minority of cases. Interestingly, a recent study demonstrated a connection between antibodies to an exogenous antigen, bovine serum albumin (BSA) and IMN in children with this disease [15]. BSA was found in immune deposits, as well as in the circulation of affected children. Furthermore, anti-BSA circulating antibodies were found in the children. All these examples demonstrate that IMN is a conglomeration of autoimmune diseases in which antibodies are produced to podocyte specific proteins, or alternatively there is in situ formation of immune complexes to antigens deposited at the filtration barrier.