Over a quarter century after the discovery of verocytotoxin and the first report by Karmali and colleagues of cases of postdiarrheal hemolytic uremic syndrome (HUS) caused by verotoxigenic Escherichia coli (VTEC), otherwise known as Shiga-toxigenic E. coli (STEC), successful treatment of these infections has remained elusive. This is because the pathological insult producing the clinical picture of HUS occurs early in the disease process and curtails quickly, making treatment intervention a largely vain hope. Nevertheless, understanding of the pathogenesis of HUS has expanded and, as a result, we can expect a future breakthrough in the treatment of this life-threatening condition. This review examines the pathogenesis of HUS and explores targets for treatment, including the reasons why certain therapies have failed and why future therapies could be successful. This review also examines the status of vaccine development in prevention of VTEC/STEC disease.