Clostridium difficile is a gram-positive anaerobic bacillus responsible for approximately 1 of 5 cases of antibiotic-associated diarrhea. C difficile infection (CDI) is defined by at least 3 unformed stools in a 24-hour period and stool, endoscopic, or histopathologic test results that indicate the presence of this bacteria. The history of CDI research can be divided into early (before 2000) and modern eras (after 2000). C difficile was first described in 1935, and the characteristics and causes of CDI as well as therapies were identified during the early era of research. During the modern era, CDI has become a more common, aggressive nosocomial infection. Our understanding of the epidemiology, diagnosis, treatment, and prevention of CDI has increased at a rapid pace. We review features of CDI diagnosis, treatment, and prevention. © 2012 AGA Institute.