Historically, disorders with microangiopathic hemolytic anemia (MAHA) and thrombocytopenia, often collectively referred to as thrombotic microangiopathy (TMA), have been classified as syndromes based on certain sets of symptoms and signs. Thus, the constellation of MAHA and thrombocytopenia, with or without neurological deficits, constitutes the diagnosis of thrombotic thrombocytopenic purpura (TTP), whereas the constellation of MAHA, thrombocytopenia, and renal failure is equated to the hemolytic uremic syndrome (HUS), which is further designated as typical or atypical depending on the presence or absence of a prodrome of hemorrhagic diarrhea. In practice, this syndrome-based classification does not provide clear distinctions in pathogenesis and misses patients who do not present with all the defining features. This chapter presents a new scheme that is based on pathologic features and newly uncovered molecular mechanisms of TTP, due to deficiency of ADAMTS13 (a disintegrin-like and metalloprotease with thrombospondin type 1 motif, member 13), and aHUS (atypical hemolytic uremic syndrome), due to defective regulation of the alternative complement pathway activation.