For a disease with <80 years of history, clinical and basic research into thrombotic thrombocytopenic purpura (TTP) has been significantly accelerated since the identification of unusually large von Willebrand factor (VWF) multimers and deficiency of ADAMTS-13 ( A Disintegrin And Metalloproteinase with Thrombo Spondin-1-like domains) as the potential cause. The VWF-cleaving metalloprotease ADAMTS-13 has since been extensively characterized and its biological action tested in vitro and in vivo. There have also been considerable efforts to understand the interaction between ADAMTS-13 and its substrate VWF, as well as its biological regulation. This review focuses on recent advances in our understanding of the biology of VWF cleavage by ADAMTS-13 and how this newly gained knowledge will eventually help the clinical management of patients with TTP. This review also discusses the potential for ADAMTS-13 as a therapeutic drug for thrombotic conditions other than TTP.