Extraintestinal pathogenic E. coli (ExPEC) present a major clinical problem that has emerged in the past years. Most of the infections are hospital or community-acquired and involve patients with a compromised immune system. The infective agents belong to a large number of strains of different serotypes that do not cross react. The seriousness of the infection is due to the fact that most of the infecting bacteria are highly antibiotic resistant. Here, we discuss the bacterial factors responsible for pathogenesis and potential means to combat the infections.