The first major outbreaks caused by enterohemorrhagic Escherichia coli (EHEC) raised public and medical awareness of the risks associated with acquiring this potentially deadly infection. The widespread presence of these organisms in the environment, the severity of the clinical sequelae, and the lack of treatment options and effective preventive measures demand that we obtain a better understanding of how this group of organisms cause disease. Animal models allow study of the processes and factors that contribute to disease and, as such, form a valuable tool in the repertoire of infectious disease researchers. Yet despite more than 30 years of research, it seems that no single model host reproduces the full spectrum of clinical disease induced by EHEC in humans. In the first part of this review, a synopsis of what is known about EHEC infections is garnered from human outbreaks and biopsy specimens. The main features and limitations of EHEC infection models that are based on the three most commonly used species (pigs, rabbits, and mice) are described within a historical context. Recent advances are highlighted, and a brief overview of models based on other species is given. Finally, the impact of the host on moderating EHEC infection is considered in light of growing evidence for the need to consider the biology and virulence strategies of EHEC in the context of its niche within the intestine.