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Clostridium difficileinfections (CDI) have emerged as a major cause of healthcare associated disease, and recent epidemiological evidence also suggests an important role in community-acquired diarrhea. This increase is associated with specific types, especially PCR ribotypes 027 and 078, which are sometimes referred to as “hypervirulent”. Over the past years major advances have been made in our understanding ofC. difficilepathogenicity, with the identification and characterization of the major clostridial toxins TcdA and TcdB. However, the relation between the toxins, their regulation, and “hypervirulence” remain unclear. Here I review our current understanding ofC. difficilepathogenicity and argue that “hypervirulent” is an inadequate term to describe PCR ribotypes 027 and 078, that the ability ofC. difficileto cause problematic infections is a consequence of a multifactorial process that extends beyond toxins, sporulation, and antimicrobial resistance, and that vigilance is in order toward types that are closely related to ribotypes 027 and 078, but are currently not considered problematic.