Verocytotoxigenic Escherichia coli (VTEC) are a good example of the evolution and emergence of pathogenic E. coli. Unknown before the late 1970s, these bacteria are a major cause of hemorrhagic colitis and hemolytic uremic syndrome worldwide. The production of verocytotoxins is the main virulence feature of VTEC but cannot be solely responsible for full pathogenicity. VTEC associated with severe human disease are usually capable of colonizing the intestinal mucosa with a characteristic attaching-and-effacing mechanism, genetically governed by the locus of enterocyte effacement, and possess other mobile genetic elements carrying additional virulence genes such as plasmids, phages, and pathogenicity islands (e.g., O-I 122). Despite the huge amount of data collected after the sequencing of the full genome of VTEC O157, the virulence and the evolution of the different VTEC serotypes have only been partially unraveled. A greater understanding of the factors governing the development of severe disease in humans and the colonization of animal hosts must be achieved before effective intervention strategies aimed at the reduction of the burden of infection can be developed. Defining all the factors characterizing a fully pathogenic VTEC strain will be crucial to improve the efficacy of the diagnosis of human infections, the surveillance of animal reservoirs, the assessment of public health risks, and the development of control interventions. An overview of the VTEC virulence factors, including their genetic basis and function, would start this process and is the objective of this article.