Extraintestinal pathogenic Escherichia coli (ExPEC), the specialized strains of E coli that cause most extraintestinal E coli infections, represent a major but little-appreciated health threat. Although the reasons for their evolution remain mysterious, by virtue of their numerous virulence traits ExPEC clearly possess a unique ability to cause disease outside the host intestinal tract. Broader appreciation of the existence and importance of ExPEC and better understandings of their distinctive virulence mechanisms, reservoirs, and transmission pathways may lead to effective preventive interventions against the morbid and costly infections ExPEC cause.