Clostridium difficile infection (CDI) is a high-impact hospital-acquired condition and a chief driver of excess morbidity, mortality, and treatment cost. The diagnosis, treatment, and prevention of CDI are key components of any hospital-based practice. Urologists see a small percentage of all patients with CDI, but traditionally utilize antibiotic agents that put patients at risk of CDI. Urologic procedures making use of bowel have a significantly higher rate of CDI than other procedures. This review addresses concepts that practicing urologists should be aware of and should be able to put into practice to diagnose, treat, and prevent CDI.