A formerly infrequently isolated strain of Clostridium difficile known as BI/NAP1 has resulted in geographically diverse outbreaks of C. difficile-associated disease. Such rapid dissemination and distribution of an outbreak strain of C. difficile are unprecedented, with many regions across North America, as well as several countries in Europe, being affected, all in such a short period of time. Also of note is that nontraditional hosts (e.g., otherwise healthy, noninstitutionalized persons residing in the community, some without antimicrobial exposure) have been reported to have severe disease. Data suggest that certain virulence characteristics may be responsible for more severe clinical presentations and poor outcomes. These factors (e.g., hypertoxin production, hypersporulation, antimicrobial resistance) possessed by a previously uncommon strain of C. difficile, in conjunction with particular host and environmental factors, may have precipitated the now widespread establishment of this pathogen. Antimicrobial intervention has traditionally been a mainstay of combating C. difficile-associated disease. Efforts to combat BI/NAP1 should include good antimicrobial stewardship in addition to effective infection control and environmental intervention.