Circulating permeability factors may be important in idiopathic nephrotic syndrome (INS) including focal segmental glomerulosclerosis (FSGS) and in recurrence after renal transplantation. Evidence for plasma factors includes posttransplant recurrence of proteinuria and its response to plasmapheresis or immunoadsorption and induction of proteinuria in experimental animals by infusion of patient plasma or its fractions. The authors and other investigators have used proteomic techniques to seek pathogenic molecules. The authors have recently proposed cardiotrophin-like cytokine-1 (CLC-1) as an active factor in FSGS. Other potential permeability factors include hemopexin and vascular permeability factor in minimal change nephrotic syndrome (MCNS) and soluble urokinase receptor in FSGS. In the authors' studies, in vitro plasma permeability activity is blocked by diverse substances that may decrease levels of active molecules or block the effects of circulating permeability factors. It has been shown that the simple sugar galactose blocks the effect of FSGS serum on albumin permeability in vitro and decreases permeability activity when administered to patients. Because identities of permeability factors and their mechanisms of action are not well defined, therapy of INS/FSGS is empiric. Corticosteroids are the mainstay of initial therapy whereas calcineurin inhibitors such as cyclosporine A (CsA) and immunosuppressive medications provide adjunctive therapy. Nonspecific therapies such as blocking the renin-angiotensin system and controlling blood pressure and plasma lipids may also diminish proteinuria and slow progression. Identification of molecules that initiate proteinuria and application of findings from in vitro studies may lead to development of new treatments to arrest progression and prevent recurrence after transplantation.