Hemolytic uremic syndrome is a triad of microangiopathic hemolytic anemia, thrombocytopenia, and acute renal failure. It is one of a group of conditions termed the thrombotic microangiopathies, which are characterized by prominent endothelial cell injury. It may be diarrheal-associated or atypical (aHUS). Evidence for a pathogenic role of the alternative pathway of complement was first suggested in 1974. Mutations in the complement regulatory proteins factor H, membrane cofactor protein (CD46), and factor I predispose to aHUS development. Mutations of the activating components factor B and complement C3 have also been reported. Penetrance is approximately 50%, suggesting other genetic and environmental modifiers are needed for disease expression. Identification of mutations is important owing to differences in mortality, renal survival, and outcome of renal transplantation. Current treatment is plasma infusion/exchange, but complement inhibitor therapy provides hope for the future.