Neither the initiating factors nor the proximate causes of injury that produce proteinuria in nephrotic syndrome have been clearly defined. Immune mechanisms have been postulated in minimal-change nephrotic syndrome (MCNS), focal segmental glomerular sclerosis (FSGS), and glomerular sclerosis associated with human immunodeficiency virus (HIV) infection. Circulating factors have been proposed in MCNS and FSGS, although no specific mediator has been identified. Prompt remission of proteinuria following steroid treatment and the presence of altered immune responsiveness in patients with MCNS have been used to support the participation of an immune mechanism in the pathogenesis of MCNS. Both FSGS and HIV-related nephropathy are usually steroid-resistant. Immune mechanisms are postulated in FSGS because of early recurrence after transplantation, and in HIV-related nephropathy because of the numerous associated immune abnormalities. Experimental models of nephrotic syndrome based on neutralization of glomerular charge, toxic injury to podocytes, injection of antibodies to glomerular components, or abnormalities in transgenic mice have been used to define mechanisms of glomerular injury. This review summarizes physiologic and immunologic abnormalities in MCNS, FSGS, and HIV-associated nephropathy and in several experimental models of nephrotic syndrome, and outlines the immunologic mechanisms and cellular reactions that may be responsible for glomerular dysfunction in these entities.