Atypical hemolytic uremic syndrome (aHUS) is a major thrombotic microangiopathy (TMA). A TMA is recognized by the laboratory signs of microangiopathic hemolysis, as indicated by schistocytes, elevated lactate dehydrogenase, low haptoglobin, and low hemoglobin, plus thrombocytopenia and accompanying signs and symptoms of organ system involvement. aHUS results from chronic, uncontrolled activity of the alternative complement pathway. In most patients, this defect is related to a genetic deficiency in one or more soluble and/or membrane-bound complement regulatory proteins. Complement factor H is most frequently implicated. Clinically, aHUS is often indistinguishable from the other TMAs: Shiga toxin–producing Escherichia coli (STEC) hemolytic uremic syndrome and thrombotic thrombocytopenic purpura (TTP). TTP and aHUS are associated with high morbidity and mortality. aHUS has a distinct pathology from TTP. In nearly all patients, aHUS can be distinguished from TTP on the basis of an ADAMTS13 (a disintegrin and metalloproteinase with a thrombospondin type 1 motif, member 13) enzyme activity measurement. It is essential that aHUS and TTP be differentiated quickly, as they require markedly divergent treatments. The standard treatment for TTP is plasma exchange, a therapy that has no role for patients with a diagnosis of aHUS established by ADAMTS13 activity levels.