Treatment of Clostridium difficile infection (CDI) has relied on 2 antimicrobial agents, metronidazole and vancomycin, since the recognition of this disease entity. While effective, these “inside the box” approaches to CDI management have the disadvantage of further microbial disruption of the host indigenous microflora. “Outside the box” therapies use nonantimicrobial approaches to management and are theoretically less prone to causing recurrent CDI episodes. Recent advances in understanding of “inside the box” approaches include appreciation of the decreased efficacy of metronidazole overall and the superior efficacy of vancomycin for treatment of severe CDI, as well as a new agent under development, fidaxomicin, which appears to be equal in efficacy to vancomycin but with less risk of subsequent CDI recurrences. Several “outside the box” approaches have also entered clinical development, including use of monoclonal antibodies, active vaccination, luminal toxin binders, and nontoxigenic C. difficile. These reports provide optimism that more-effective management of CDI is forthcoming.