Clostridium difficile is the leading cause of hospital-acquired diarrhea in Europe and North America and is a serious reemerging pathogen. Recent outbreaks have led to increasing morbidity and mortality and have been associated with a new strain (BI/NAP1/027) of C difficile that produces more toxin than historic strains. With the increasing incidence of C difficile infection, clinicians have also seen a change in the epidemiology with increased infections in previously low-risk populations. This chapter highlights the current knowledge on C difficile virulence, human disease, epidemic outbreaks and optimal treatment strategies.