Clostridium difficile is a gram-positive, anaerobic, spore-forming bacterium that is the leading cause of nosocomial infections in hospitals in the United States. Critically ill patients are at high risk for C. difficile infection (CDI) and face potentially detrimental effects, including prolonged hospitalization, risk of recurrent disease, complicated surgery, and death. CDI requires a multidisciplinary approach to decrease hospital transmission and improve treatment outcomes. This article briefly reviews the current literature and guideline recommendations for treatment and prevention of CDI, with a focus on antibiotic treatment considerations including dosing, routes of administration, efficacy data, adverse effects, and monitoring parameters.