Rituximab offers an alternative to current immunosuppressive therapies for difficult-to-treat nephrotic syndrome. The best outcomes are seen in patients with steroid-dependent nephrotic syndrome who have failed to respond to multiple therapies. By contrast, the benefits of rituximab therapy are limited in patients with steroid-resistant nephrotic syndrome, particularly those with focal segmental glomerulosclerosis (FSGS). Therapy with plasma exchange and one or two doses of rituximab has shown success in patients with recurrent FSGS. Young patients and those with normal serum albumin at recurrence of nephrotic syndrome are most likely to respond to rituximab therapy. A substantial proportion of rituximab-treated patients with idiopathic membranous nephropathy show complete or partial remission of proteinuria, and reduced levels of phospholipase A(2) receptor autoantibodies, which are implicated in the pathogenesis of this disorder. Successful rituximab therapy induces prolonged remission and enables discontinuation of other medications without substantially increasing the risk of infections and other serious adverse events. However, the available evidence of efficacy of rituximab therapy is derived chiefly from small case series and requires confirmation in prospective, randomized, controlled studies that define the indications for use and predictors of response to this therapy.