The majority of investigations on EHEC disease development have focussed on the pathogenesis of HUS. After ingestion and passing through the acidic stomach, EHEC release Shiga toxins (Stxs) that are subsequently absorbed across the gut epithelium into the circulation. Stxs are believed to be the major precipitants of the widespread thrombotic microvascular lesions that form the histopathological basis of HUS. Injury to endothelial cells is believed to be the key event which underlies the pathogenesis of HUS. In target organs, Stx1 and Stx2 bind to the glycolipid receptor globotriaosylceramide (Gb3), which is expressed in microvascular endothelial cells of the kidney, intestine, and brain. Stx internalization by receptor-mediated endocytosis is followed by toxin interaction with subcellular components that results in inhibition of protein synthesis or apoptosis. Although endothelial cells appear to be the main targets for Stxs, also other cell types, such as renal tubular cells, mesangial cells, monocytes, and platelets, can be affected by Stxs. Circulating proinflammatory cytokines (especially tumor necrosis factor-α and interleukin 1β stimulated by direct action of Stx on monocytes, potentiate the action of the toxin on endothelial cells by inducing expression of the Stx receptor Gb3. Binding of Stx to its target cells presumably initiates a complex chain of events, including coagulation and proinflammatory processes, resulting in HUS.