The incidence of Clostridium difficile-associated disease (CDAD) and its serious complications (including colectomy and death) have been increasing worldwide. This phenomenon is strongly associated with the appearance of a new "hypervirulent" strain in several countries. More-effective strategies are needed for the prevention and treatment of this entity. This article will review the current approaches using antimicrobials, probiotics, immunomodulation, surgery, and miscellaneous adjuvants to prevent and treat this infection.