C. difficile infection (CDI) has become more common as well as more severe. Antibiotics represent the most important, and the most potentially modifiable, risk factor. However, the widespread use of proton pump inhibitors may represent a significant risk factor for CDI in the general population. Knowledge of the most frequently used severity scoring systems may help the surgeon in selecting antibiotic therapy. The choice to surgically intervene requires a careful balance between timely care and providing adequate time for aggressive medical therapy to be effective. The role of colectomy versus the construction of a diverting ileostomy with colonic lavage requires further study. Fecal microbiota transplant (FMT) has much to commend it, even for the care of severe forms of CDI.