Enteropathogenic Escherichia coli (EPEC) strains induce morphological changes in infected epithelial cells. The resulting attaching and effacing (A/E) lesion is characterized by intimate bacterial adherence to epithelial cells, with microvillus destruction, cytoskeletal rearrangement, and aggregation of host cytoskeletal proteins. This review presents an overview of the adhesion mechanisms used for the colonization of the human gastrointestinal tract by EPEC. The mechanisms underlying EPEC adhesion, prior to and during the formation of the A/E lesion, and the host cytosolic responses to bacterial infection leading to diarrheal disease are discussed.