In use for over 50 years, the rationale for plasmapheresis remains based largely on case series and retrospective studies. Recently, results from several randomized controlled trials, meta-analyses, and prospective studies have shown plasmapheresis may be of benefit in various renal diseases, and have provided insights into more rational use of this therapy. A multicenter trial by the European Vasculitis Study Group has shown it is the preferred additional form of therapy for patients with anti-neutrophil cytoplasmic antibody-associated glomerulonephritis and severe renal failure. A recent study conducted at Mayo Clinic also found it effective at reversing renal failure from myeloma-related cast nephropathy if serum free light chain levels were reduced by at least 50%. In addition, a Cochrane review has analyzed the available evidence for its use in thrombotic thrombocytopenic purpura and hemolytic uremic syndrome. The objective of this article is to review recent and past evidence and, thereby, the current indications for treatment in renal disease.