Clostridium difficile-associated disease (CDAD) causes substantial morbidity and mortality. The pathogenesis is multifactorial, involving altered bowel flora, production of toxins, and impaired host immunity, often in a nosocomial setting. Current guidelines recommend treatment with metronidazole; vancomycin is a second-line agent because of its potential effect on the hospital environment. We present the data that led to these recommendations and explore other therapeutic options, including antimicrobials, antibody to toxin A, probiotics, and vaccines. Treatment of CDAD has increasingly been associated with failure and recurrence. Recurrent disease may reflect relapse of infection due to the original infecting organism or infection by a new strain. Poor antibody responses to C difficile toxins have a permissive role in recurrent infection. Hospital infection control and pertinent use of antibiotics can limit the spread of CDAD. A vaccine directed against C difficile toxin may eventually offer a solution to the CDAD problem.