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Renewed interest in Clostridium difficile infections (CDI) is stimulating research into the pathogenesis and virulence factors for this pathogen. This review summarizes recent progress in the field, particularly in relation to the changing epidemiologic trends and new investigational treatments.Elucidation of the role of different toxins of C. difficile (tcdA, tcdB and binary toxin) is deepening our understanding of CDI. Stain typing of C. difficile isolates is documenting the spread of an emergent strain (BI/NAP1/027) associated with large outbreaks of severe disease. Typing of isolates around the world shows global spread of this strain. Reliance upon metronidazole is questioned due to a lower response rate and newer investigational therapies are reported.After being considered a manageable pathogen for decades, C. difficile recently caused large outbreaks of severe disease. Refocused research is determining patients who are at risk for CDI, what methods are more effective in diagnosing CDI and what new treatments may be effective. This article reviews the recent findings in the literature regarding this difficult and challenging pathogen.