Clostridium difficile infection (CDI) is becoming more common worldwide. The morbidity and mortality associated with C difficile is also increasing at an alarming rate. Critically ill patients are at particularly high risk for CDI because of the prevalence of multiple risk factors in this patient population. Treatment of C difficile continues to be a difficult problem in patients with severe or recurrent disease. This article seeks to provide a broad understanding of CDI in the intensive care unit, with special emphasis on risk factor identification, treatment options, and disease prevention.