Endeavors to optimize the management of thrombotic thrombocytopenic purpura (TTP) syndrome and improve mortality and relapse rates are hindered by its poorly understood pathophysiology. Variability in the application of therapeutic plasma exchange (TPE), including replacement fluid strategies, desirable endpoints in the platelet count, serum lactate dehydrogenase concentration, and the use of a TPE taper, limit comparisons among published studies. The diversity of adjunctive therapies such as antiplatelet agents, steroids, and splenectomy further clouds comparisons. Recent progress in the diagnosis, pathophysiology, and management of TTP syndrome are summarized. The possible role of occult infection and newly emerging associations such as ticlopidine therapy are discussed. Advances in possible pathogenic mechanisms, the rationale for different replacement fluids including the recently licensed solvent-detergent treated plasma, and progress in the apheresis management of TTP syndrome are presented.