Thrombotic microangiopathy (TMA) is characterized by an endothelium injury-associated formation of platelet clots in arterial and venous microvessels. Concomitant ischemia causes severe organ dysfunction and can be acutely life threatening. The underlying etiology of TMA shows a very heterogeneous disease spectrum. In addition to thrombotic thrombocytopenic purpura, which is characterized by a greatly reduced activity of a disintegrin and metalloproteinase with a thrombospondin type 1 motif, member 13 (ADAMTS13), infection-associated classical hemolytic uremic syndrome (HUS) and complement-mediated atypical HUS (aHUS), further very rare diseases or secondary forms can be present. The differential diagnostic classification is pivotal as different treatment approaches are necessary. Initiation of novel specific pharmacotherapy methods has greatly improved the prognosis of TMA.