The incidence of Clostridium difficile-associated disease (CDAD) has increased over the past few years and more severe cases of CDAD have been reported. This changing epidemiology is possibly a result of the emergence of a more virulent strain of C difficile that is more resistant to fluoroquinolones and is associated with increased morbidity and mortality. Because of advanced age and frequent courses of antibiotic therapy, patients in long-term care facilities are at increased risk of C difficile infection. In addition to beta-lactams and clindamycin, the fluoroquinolones have recently been associated with increased rates of CDAD. Early identification of C difficile infection and prompt initiation of therapy with the most appropriate agent are critical to minimize morbidity and mortality in this era of increasingly severe CDAD. Metronidazole and vancomycin have been the mainstays of therapy, and recent data support the expanding role of vancomycin in the treatment of severe CDAD. Adjunctive therapy with probiotics, intravenous immunoglobulin, or rifampin has been used in refractory or recurrent CDAD. Adherence to the recommended infection control measures and the judicious use of antibiotics should also be part of the global management of CDAD in long-term care facilities.