Enteropathogenic Escherichia coli (EPEC) strains are a leading cause of diarrhea among infants in developing countries. These bacteria spread via fecal–oral transmission and colonize the small intestine. Typical EPEC differs from atypical strains in that they possess the bfp operon and generate a type IV-B class of fimbriae known as the bundle-forming pilus (BFP). EPEC uses BFP to attach to intestinal epithelium. Upon attachment, EPEC translocates effector proteins into the host cell via a type 3 secretion system, which is encoded on a pathogenicity island known as the locus of enterocyte effacement. Translocated effectors modulate the host response in a number of ways, including subversion of immune responses and hijacking of the cytoskeletal system. By inducing actin rearrangement, EPEC causes the formation of actin pedestals onto which it sits, and leads to the effacement of microvilli, giving this bacterium a characteristic attaching and effacing phenotype. EPEC infections are typically self-limiting, with rehydration therapy constituting primary treatment, but they can be protracted and lethal. Breastfeeding provides a great protective effect, validating the use of a vaccine to induce a humoral response in mother or child as a potential means of preventative action. This chapter provides a detailed discussion on EPEC pathogenesis and host cell responses and summarizes the current detection and treatment options available.