Clostridium difficile is more common, more virulent, and more difficult to treat than in past decades. Oral vancomycin and metronidazole have been the subject of the most rigorous study in this disease. Although these antibiotics have largely been viewed as equivalent, studies support vancomycin for severe disease, whereas metronidazole is noninferior in milder disease. Both antibiotics are superior to the toxin-binding agent tolevamer. No evidence supports probiotics for initial disease, but there may be utility in relapsing disease. There is an exiguous evidence base regarding antibiotic treatment of relapsing disease, but tapered and pulsed regimens of vancomycin remain possible options. Preliminary evidence supports the use of monoclonal antibodies against C. difficile toxins A and B for relapsing episodes. The studies concerning refractory disease are limited to a case series design, whereas it remains unclear how effective probiotics are in the prevention of C. difficile infection.