Circulating permeability factors have been identified in the plasma of patients with focal segmental glomerulosclerosis (FSGS). Post-transplant recurrence of protei-nuria, improvement of proteinuria after treatment with plasmapheresis, and induction of proteinuria in experimental animals by plasma fractions each provide evidence for such plasma factors. Advanced proteomic methods have identified candidate molecules in recurrent FSGS. We have proposed cardiotrophin-like cytokine-1 as an active factor in FSGS. Another potential permeability factor in FSGS is soluble urokinase receptor. In our studies, in vitro plasma permeability activity is blocked by substances that may decrease active molecules or block their effects. We have shown that the simple sugar galactose blocks the effect of FSGS serum in vitro and decreases permeability activity when administered to patients. Since the identities of permeability factors and their mechanisms of action are not well defined, treatment of FSGS is empiric. Corticosteroids are the most common agents for initial treatment. Calcineurin inhibitors, such as cyclosporine A, and tacrolimus and immunosuppressive medications, including mycophenylate, induce remission is some patients with steroid-resistant or -dependent nephrotic syndrome. Therapies that diminish proteinuria and slow progression in FSGS as well as other conditions include renin-angiotensin blockade, blood pressure lowering and plasma lipid control. Use of findings from in vitro studies, coupled with definitive identification of pathogenic molecules, may lead to new treatments to arrest FSGS progression and prevent recurrence after transplantation.