Typing studies suggest that most cases of hospital-onset Clostridium difficile infection (CDI) are unrelated to other cases of active disease in the hospital. New cases may instead be due to transmissions from asymptomatic carriers or progression of latent C. difficile present on admission to active infection. Direct exposure to antibiotics remains the primary risk factor for CDI but ward-level antibiotic use, antibiotic exposure of the prior room occupant, and C. difficile status of the prior room occupant increase risk for C. difficile acquisition while antibiotic exposure, gastric acid suppression, and immunosuppression increase risk for progression to infection. These insights suggest possible new approaches to prevent CDI, including screening to identify and isolate carriers, universal gloving, greater use of sporicidal cleaning methods, enhancing antibiotic and possibly proton pump inhibitor stewardship, and prescribing prophylactic vancomycin and/or probiotics to colonized patients to prevent progression from colonization to infection. We review current evidence and questions related to these interventions.