Shiga toxin-producing Escherichia coli (STEC) can produce a wide spectrum of human diseases, being an important cause of both outbreaks and sporadic cases of bloody and non-bloody diarrhea, hemorrhagic colitis, the diarrhea-associated form of hemolytic uremic syndrome (HUS) worldwide. HUS is a major cause of acute renal failure in children. Albeit O157:H7 is by far the most important serotype in human infections, several different O:H serotypes of E. coli can harbor Shiga toxin (stx) genes, and actually some non-O157 strains cause illnesses that are comparable in severity to O157-induced diseases, posing a substantial concern to public health. Infections due to STEC have a proven zoonotic character as these bacteria are largely distributed among both domestic and wildlife animal species. STEC infections are transmitted to humans through contaminated food, water, and contact with infected animals or people. The cascade leading from gastrointestinal infection to renal impairment is complex, being the production of Stx the major pathogenicity determinant of STEC. However, a mosaic of different virulence traits comprising several adhesins and other toxins that may play a role in pathogenesis has also been described. There is no specific treatment to reduce the progression of HUS. Research is still necessary to improve our knowledge on the mechanisms of Stx infections and the pathophysiology of cell injury in HUS to lead to better therapeutic strategies to prevent the acute mortality and the long-term morbidity of HUS.