The incidence of Clostridium difficile has doubled over the past 15 years, and rising mortality rates associated with this infection have followed in its wake. C. difficile infection (CDI) has supplanted methicillin-resistant Staphylococcus aureus as the major cause of nosocomial infection. An insufficient response rate to currently available CDI therapies has prompted the search for new and alternative treatment modalities for this disease. The investigational pipeline includes evaluation of new antimicrobial agents that exhibit good activity against C. difficile without altering normal gut flora, C. difficile toxin-absorbing compounds, and preformed antibodies and vaccines against C. difficile toxin. In two robust clinical trials comparing fidaxomicin to vancomycin in the treatment of CDI, treatment with fidaxomicin demonstrated a superior global cure (cure without recurrence) rate compared with the current gold standard, vancomycin. Fidaxomicin, the first of a new class of macrocyclic antimicrobial agents, represents an advance in the management of CDI.