Summary: Thrombotic thrombocytopenic purpura (TTP), a potentially fatal clinical syndrome, is primarily caused by autoantibodies against the von Willebrand factor (VWF)-cleaving metalloprotease ADAMTS-13. In general, severe deficiency of plasma ADAMTS-13 activity (< 10 IU dL−1) with or without detectable inhibitory autoantibodies against ADAMTS-13 supports the diagnosis of TTP. A patient usually presents with thrombocytopenia and microangiopathic hemolytic anemia (i.e. schistocytes, elevated serum lactate dehydrogenase, decreased hemoglobin and haptoglobin) without other known etiologies that cause thrombotic microangiopathy (TMA). Normal to moderately reduced plasma ADAMTS-13 activity (> 10 IU dL−1) in a similar clinical context supports an alternative diagnosis such as atypical hemolytic uremic syndrome (aHUS) or other types of TMA. Prompt differentiation of TTP from other causes of TMA is crucial for the initiation of an appropriate therapy to reduce morbidity and mortality. Although plasma infusion is often sufficient for prophylaxis or treatment of hereditary TTP due to ADAMTS-13 mutations, daily therapeutic plasma exchange remains the initial treatment of choice for acquired TTP with demonstrable autoantibodies. Immunomodulatory therapies, including corticosteroids, rituximab, vincristine, cyclosporine, cyclophosphamide and splenectomy, etc., should be considered to eliminate autoantibodies for a sustained remission. Other emerging therapeutic modalities, including recombinant ADAMTS-13, adeno-associated virus (AAV) 8-mediated gene therapy, platelet-delivered ADAMTS-13, and antagonists targeting the interaction between platelet glycoprotein 1b and VWF are under investigation. This review highlights the recent progress in our understanding of the pathogenesis and diagnosis of, and current and potential novel therapies for, hereditary and acquired TTP.