Clostridioides (formerly Clostridium) difficile infection is among the most identified causes of health care-associated infections in US hospitals and remains a major public health problem. The incidence and severity of C difficile infection are high among critically ill patients. Treating critically ill patients is challenging; treatment failure is especially common because of comorbidities and the continued need for antibiotic therapy for other infections. Because of the high risk of C difficile infection recurrence and high mortality rate associated with the disease, intensive research has taken place over the last decade to improve patient outcomes. This research has resulted in new drugs indicated for C difficile infection and new information on existing drugs. The 2010 clinical practice guidelines for C difficile infections have been updated on the basis of this new information.To review the 2017 update of the clinical practice guidelines from the Society for Health-care Epidemiology of America and the Infectious Diseases Society of America.The updated recommendations for the treatment of C difficile infection, the clinical pharmacology of old and new drugs for treating the infection, and the role of critical care nurses in mini-mizing the risk of C difficile infection for their patients.