Clostridium difficile (C. difficile) is now the leading cause of nosocomial diarrhea in the USA, accounting for 30% of patients with antibiotic-associated diarrhea, 70% of those with antibiotic-associated colitis, and most cases of pseudomembranous colitis. The organism has evolved over the last 8 years to become more virulent and resistant to antimicrobials (NAP1/027 strain) causing a more severe form of the disease that has increased mortality and healthcare costs. While it is generally accepted that the problem results from the overuse of antibiotics, and in particular second and third generation cephalosporins, fluoroquinolones and macrolides, recent studies suggest that acid suppression with proton pump inhibitors (PPIs) may be equally culpable. A further common, but less recognized, etiological factor is the prolonged use of elemental diets. Such diets are totally absorbed within the small intestine and therefore deprive the colonic microbiota of their source of nutrition, namely dietary fiber, fructose oligosaccharides, and resistant starch. The resultant suppression of colonic fermentation leads to suppression of the "good" bacteria, such as butyrate-producers (butyrate being essential for colonic mucosal health), and bifidobacteria and the creation of a "permissive" environment for C. difficile colonization and subsequent infection. Based on this analysis, the best chance of suppressing the emerging C. difficile epidemic is to adopt a 3-pronged attack consisting of (1) avoidance of the use of prophylactic antibiotics, (2) the avoidance of prophylactic PPIs, and (3) the conversion of elemental diet feeding to a diet containing adequate indigestible carbohydrate after the first week of critical illness. In this review, we highlight the rising worldwide incidence of C. difficile associated diarrhea and the role played by non-residue diets in destabilizing the colonic microbiota.