In the past, Clostridium difficile-associated disease (CDAD) was thought of mainly as a nosocomial disease associated with the use of broad-spectrum antibiotics, but its epidemiology seems to be changing. Since 2002, outbreaks of severe CDAD associated with increased mortality and reduced effectiveness of treatment with metronidazole have focused attention on this challenging pathogen. A fluoroquinolone-resistant strain of C. difficile (BI/NAP1/027) has been predominantly associated with these outbreaks. Changes in the epidemiology of CDAD include the emergence of new at-risk populations and the increased incidence of the disease. Infection control programs and more effective treatments offer hope that future outbreaks of CDAD can be controlled.