The most dramatic change in the past several years has been the increased incidence and severity of Clostridium difficile colitis reported from multiple countries. A number of factors have likely contributed to this. One major event has been the emergence of a fluoroquinolone-resistant clone of C. difficile with enhanced virulence properties that is associated with epidemic disease. Also noteworthy is the apparently decreasing effectiveness of the first-line agent metronidazole in treating this disease. Aggressive treatment of severe C. difficile colitis requires a multifaceted approach, including: 1) cessation of antibiotics where possible; 2) oral vancomycin; 3) if an ileus exists, intravenous administration of metronidazole and possibly intracolonic administration of vancomycin; 4) intravenous immunoglobulin if response to therapy is not rapid, or if there are signs of sepsis; and 5) early surgical consultation. Although it is likely that intravenous immunoglobulin contains antibodies against C. difficile toxins, its benefit remains unproven in rigorous clinical trials. Efforts to actively or passively immunize patients at risk are being explored to prevent the increasing morbidity and mortality associated with this disease. However, defining exactly who is at risk for severe C. difficile-associated disease is complex, as cases are being reported in populations not previously believed to be vulnerable.