There have been recent, marked increases in the incidence and severity of Clostridium difficile-associated disease (CDAD). These may be attributable to the emergence of a hypervirulent strain of C. difficile that produces increased levels of toxins A and B, as well as an extra toxin known as "binary toxin." This previously uncommon strain has become epidemic, coincident with its development of increased resistance to fluoroquinolones, the use of which is increasingly associated with CDAD outbreaks. Although not necessarily related to this epidemic strain, unusually severe CDAD has been reported in populations that had previously been thought to be at low risk, including peripartum women and healthy persons living in the community. Challenges posed by the changing epidemiology of CDAD are compounded by current limitations in diagnostic testing, treatment, and infection control. Overcoming these challenges and limitations will require a concerted effort from a variety of sources, including an ongoing partnership between infectious disease clinicians and public health professionals.