Pathogenic strains of Escherichia coli, including enteropathogenic E. coli (EPEC), enterohemorrhagic E. coli (EHEC), and enterotoxigenic E. coli (ETEC), are responsible for a broad spectrum of diseases, which include local (intestinal) and systemic syndromes. In particular, infection with EHEC strains is also the leading cause of Hemolytic Uremic Syndrome (HUS), a systemic complication that affects to 5-10 % of EHEC infected children. These extracellular bacteria have the ability to intimately attach to the intestinal epithelium, flatten absorptive microvilli (effacement), and cause intestinal damage characterized by cellular necrosis, disruption of the epithelium, diarrhea and occasionally bleeding. The induction of these lesions depends on a type III secretion system (T3SS) encoded within the loci of enterocyte effacement (LEE). In case of EHEC strains, the expression of Shiga toxins (Stx) is one of the major pathogenic factors, which can modulate the severity of the intestinal damage, but also is responsible for HUS development. In thischapter we present and discuss new data helping to understand the role of Stx and the other bacterial pathogenic factors, as well as the involvement of host responses, in the evolution from gastrointestinal disease to systemic HUS complication.