It is surprising how little we know about this unique region of the glomerulus. It contains cells with fibrils and myosin and an intercellular collagenous matrix material, situated adjacent to elements of the juxtaglomerular apparatus with which an integrated functional relationship is likely, but unproven. Studies of the mesangium in human disease have been limited to morphologic and immunohistologic studies. Abnormalities in this site have been relatively specific in some diseases: the intercapillary nodule observed in diabetic nephropathy; the mesangial ring of C3 outlining dense deposit material in type II membranoproliferative glomerulonephritis; and the presence of IgA, C3, and properdin without earlier complement components in IgA nephropathy. Other mesangial abnormalities - Ig and complement component deposition, cellular proliferation, matrix expansion, sclerosis - are not characteristic of any specific disease process. Studies in animals have begun to untangle some of the complexities involved in the movement of macromolecules into and out of the mesangium. Ultrastructural studies that use a variety of probes support the concept of plasmic flow through this region. The afferent pathway is influenced by a number of variables, including the blood level and, characteristic of the macromolecule, the glomerular blood flow, and likely other hemodynamic determinants of glomerular filtration and unknown factors that encourage movement from the capillary lumen into the mesangium. The efferent pathway includes transit by way of the glomerular stalk to the juxtaglomerular zone, but thereafter the route is obscure; phagocytosis by infiltrating cells or resident mesangial cells; and possibly regurgitation into the glomerular capillary at low blood levels of the circulating macromolecule. Increased uptake has been demonstrated in rats given aminonucleoside of puromycin or anti-GBM antibody without alteration in the efferent limb. In contrast, ureteral obstruction induces efferent blockade. The information accumulated in the recent past by studies of the structure and function of the glomerular mesangium in laboratory animals demonstrates a number of potential mechanisms to explain some aspects of human glomerular disease. It seems likely that additional understanding of these concepts will lead to improved therapeutic approaches, as well as control and prevention of several important forms of renal disease in man.