Enterohemorrhagic Escherichia coli (EHEC) can cause food-borne disease outbreaks associated with contaminated beef or fresh produce, resulting in diarrhea, hemorrhagic colitis, and/or hemolytic uremic syndrome: the triad of anemia, thrombocytopenia, and renal failure. Intestinally colonized cattle are a major source of human infection. Upon colonic infection, EHEC utilizes a type III secretion system to translocate into mammalian cells bacterial effector proteins that target cellular functions such as epithelial barrier integrity, vesicular transport, and cytoskeletal structure. Translocated effectors induce ‘attaching and effacing’ lesions, characterized by microvillar effacement, intimate attachment, and actin ‘pedestal’ formation beneath bound bacteria. Systemic disease relies on the production of Shiga toxin, a potent inhibitor of ribosome function that triggers cell death, inflammation, and vascular damage. Most current therapies are only supportive in nature because antibiotic treatment may increase Shiga toxin production. Therefore, outbreak prevention, early diagnosis, and the development of new therapeutic strategies are critical.