Clostridium difficile is a gram-positive, spore-forming anaerobic bacillus that produces two large toxins, A and B, which cause diarrhea and colitis in susceptible patients whose normal colonic bacterial microbiota has been previously disrupted by prior antimicrobial treatment. Rates of C. difficile infection in the United States have tripled since 2000, mortality has increased, and a toxin variant strain of C. difficile known as BI/NAP1/027 has become widespread in North America and Europe. Pseudomembranous colitis is seen in about half the patients with symptomatic C. difficile infection and is characterized by formation of punctate pseudomembranes that can cover the entire colonic surface in severe cases. High-risk environments include acute care hospitals and long-term care facilities in which the use of antimicrobials is high (increasing the size of the susceptible population) and the environment is heavily contaminated by the spores of C. difficile (increasing the risk of patient contact with the organism). Good personnel hand hygiene, gloving, barrier precautions, and thorough environmental cleaning to prevent transmission of the spores to the patient can accomplish prevention and control. C. difficile infection (CDI) can be most effectively prevented by reducing overall antimicrobial usage and by avoiding use of certain specific antimicrobials, such as clindamycin, third-generation cephalosporins, and fluoroquinolones. Treatment is with another antimicrobial agent, either oral vancomycin or fidaxomicin.