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The increasing incidence of Clostridium difficile infection (CDI) is confronting us with two major problems in CDI management that presently remain unsolved: refractoriness to therapy and recurrence of disease. This review focuses on recent insights in antimicrobial therapy of CDI, as well as advances in alternative treatment modalities.In severe CDI, oral vancomycin has shown its superiority over metronidazole in two independent trials. Of new antimicrobials, nitazoxanide and fidaxomicin have shown promise, but the role of these and several other drugs such as rifaximin and tigecycline still has to be established. Additional antimicrobials display in-vitro activity against C. difficile but have not yet been studied in CDI patients. Immunotherapy currently focuses on intravenously administered antibodies directed against clostridial toxins, which may help reduce recurrence rates when given as adjunct to standard treatment. No new trials of probiotics in CDI have been published but current literature does not support their usage. The results of a first randomized trial of faecotherapy are awaited.Currently, no evidence-based guidance can be given with respect to refractoriness to treatment and preventing recurrences after treatment for CDI. Results of clinical trials on new approaches with antimicrobials, immunotherapy or faecotherapy are urgently awaited.