Thrombotic thrombocytopenic purpura (TTP) is a disorder of blood coagulation that presents classically with the pentad of fever, thrombocytopenia, microangiopathic hemolytic anemia, renal dysfunction and mental status changes. However, the clinical presentation can be quite variable making the diagnosis difficult in many cases. "Hyaline" microthrombi composed primarily of platelets and Von Willebrand Factor (VWF) are found in the small vessels of affected organs and represent the pathological hallmark of the disease. The accompanying tissue ischemia is thought to explain the clinical TTP signs and symptoms. Pathogenesis of TTP has been linked to dysfunction of ADAMTS13, a metalloprotease whose only known substrate is VWF. Interestingly, further investigation into the natural history of TTP has demonstrated that ADAMTS13 deficiency likely is necessary, but not sufficient for the development of this disease, suggesting that additional genetic and/or environmental factors are required for TTP pathogenesis. Recently, a mouse model of TTP was established that recapitulates many of the key clinical features of this disease, including the requirement for further genetic and environmental factors in addition to ADAMTS13 deficiency. Therefore, in addition to being useful for the direct study of disease pathophysiology in vivo, this mouse model may also play a key role in elucidating some of the important environmental and genetic contributors to disease pathogenesis. Here we will review TTP in humans, and then discuss recent information gained from the analysis of ADAMTS13-deficient mice.