Since publication of the Society for Healthcare Epidemiology of America position paper on Clostridium difficile infection in 1995, significant changes have occurred in the epidemiology and treatment of this infection. C. difficile remains the most important cause of healthcare-associated diarrhea and is increasingly important as a community pathogen. A more virulent strain of C. difficile has been identified and has been responsible for more-severe cases of disease worldwide. Data reporting the decreased effectiveness of metronidazole in the treatment of severe disease have been published. Despite the increasing quantity of data available, areas of controversy still exist. This guideline updates recommendations regarding epidemiology, diagnosis, treatment, and infection control and environmental management.